Pyridine compounds for treating leukotriene-related diseases

ABSTRACT

##STR1## This invention relates to compounds of formula (I) which are useful as leukotriene antagonists.

This is a continuation of application Ser. No. 08/211,063, filed Jul.18, 1994, now abandoned.

SCOPE OF THE INVENTION

This invention relates to certain compounds containing a substitutedpyridyl group linked to a substituted phenyl group by an alkyl orheteroatom-containing tether and their use for treating diseases arisingfrom or related to leukotrienes, particularly leukotriene B₄. As suchtheir utility lies in antagonizing the effects of leukotrienes.

BACKGROUND OF THE INVENTION

The family of bioactive lipids known as the leukotrienes exertpharmacological effects on respiratory, cardiovascular, andgastrointestinal systems. The leukotrienes are generally divided intotwo sub-classes, the peptidoleukotrienes (leukotrienes C₄,D₄ and E₄) andthe dihydroxyleukotrienes (leukotriene B₄). This invention is primarilyconcerned with the hydroxyleukotrienes (LTB) but is not limited to thisspecific group of leukotrienes.

Leukotrienes are critically involved in mediating many types ofcardiovascular, pulmonary, dermatological, renal, allergic, andinflammatory diseases including asthma, adult respiratory distresssyndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.

LTB₄ has been established as an inflammatory mediator in vivo. It hasalso been associated with airway hyper-responsiveness in the dog as wellas being found in increased levels in lung lavages from humans withsevere pulmonary dysfunction.

By antagonizing the effects of LTB₄, or other pharmacologically activemediators at the end organ, for example airway smooth muscle, thecompounds and pharmaceutical compositions of the present invention arevaluable in the treatment of diseases in subjects, including human oranimals, in which leukotrienes are a factor.

SUMMARY OF THE INVENTION

This invention relates to novel benzylsulfides of formula 1 ##STR2## oran N-oxide, or a pharmaceutically acceptable salt where Z is O, NH, NCH₃or S(O)_(q) where q is 0, 1 or 2,

m is 0-5;

R is C₁ C₂₀ -aliphatic, unsubstituted or substituted phenyl C₁ to C₁₀-aliphatic where substituted phenyl has one or more radicals selectedfrom the group consisting of lower alkoxy, lower alkyl, trihalomethyl,and halo, or R is C₁ to C₂₀ -aliphatic-O--, or R is unsubstituted orsubstituted phenyl C₁ to C₁₀ -aliphatic-O-- where substituted phenyl hasone or more radicals selected from the group consisting of lower alkoxy,lower alkyl, trihalomethyl, and halo;

R₁ is --(C₁ to C₅ aliphatic)R₄, --(C₁ to C₅ aliphatic)CHO, --(C₁ to C₅aliphatic)CH₂ OR₈, --R₄, --CH₂ OH, or CHO;

R₂ is H, halo, lower alkyl, lower alkoxy, --CN, --(CH₂)_(n) R₄,--CH(NH₂)(R₄), or --(CH₂)_(n) R₉ where n is 0-5 and where R₉ is --N(R₇)₂where each R₇ is independently H, or an aliphatic group of 1 to 10carbon atoms, or acyl of 1-6 carbon atoms, or a cycloalkyl-(CH₂)_(n)-group of 4 to 10 carbons where n is 0-3, or both R₇ groups form a ringhaving 4 to 6 carbons; or

R₃ is hydrogen, lower alkyl, lower alkoxy, halo, --CN, R₄, NHCONH₂, orOH;

each R₄ group is independently --COR₅ where R₅ is --OH, apharmaceutically acceptable ester-forming group --OR₆, or --OX where Xis a pharmaceutically acceptable cation, or R₅ is --N(R₇)₂ where each R₇is independently H, or an aliphatic group of 1 to 10 carbon atoms, or acycloalkyl-(CH₂)_(n) -group of 4 to 10 carbons where n is 0-3, or bothR₇ groups form a ring having 4 to 6 carbons, or R₄ is sulfonamide, or anamide, or tetrazol-5-yl; and

R₈ is hydrogen, C₁ to C₆ alkyl, or C₁ to C₆ -acyl,

excluding those compounds where R₂ and R₃ are other than hydrogen andare substituted in the 2 and 6 positions.

In another aspect, this invention covers pharmaceutical compositionscontaining the instant compounds and a pharmaceutically acceptableexcipient.

Treatment of diseases related to or caused by leukotrienes, particularlyLTB₄, or related pharmacologically active mediators at the end organ arewithin the scope of this invention. This treatment can be effected byadministering one or more of the compounds of formula I alone or incombination with a pharmaceutically acceptable excipient.

Processes for making these compounds arc also included in the scope ofthis invention, which processes comprise:

a) forming a salt, or

b) hydrolyzing an ester to give a salt or acid;

c) forming an ester,

d) forming an amide;

e) oxidizing a thio ether,

f) forming a compound of formula I by treating a 6-halomethylpyridylcompound with tha appropriate mercaptobenzoate or hydroxybenzoate.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used in describing this invention andsetting out what the inventors believe to be their invention herein.

"Aliphatic" is intended to include saturated and unsaturated radicals.This includes normal and branched chains, saturated or mono or polyunsaturated chains where both double and triple bonds may be present inany combination. The phrase "lower alkyl" means an alkyl group of 1 to 6carbon atoms in any isomeric form, but particularly the normal or linearform. "Lower alkoxy" means the group lower alkyl-O--. "Halo" meansfluoro, chloro, bromo or iodo. "Acyl" means the radical having aterminal carbonyl carbon.

When reference is made to a substituted phenyl ring, it is meant thatthe ring can be substituted with one or more of the named substituentsas may be compatible with chemical synthesis. Multiple substituents maybe the same or different, such as where there are three chloro groups,or a combination of chloro and alkyl groups and further where thislatter combination may have different alkyl radicals in the chloro/alkylsubstituent pattern.

The phrase "a pharmaceutically acceptable ester-forming group" in R₂ andR₃ covers all esters which can be made from the acid function(s) whichmay be present in these compounds. The resultant esters will be oneswhich are acceptable in its application to a pharmaceutical use. By thatit is meant that the mono or diesters will retain the biologicalactivity of the parent-compound and will not have an untoward ordeleterious effect in their application and use in treating diseases.Such esters are, for example, those formed with one of the followingradicals: C₁ to C₆ alkyl, phenyl C₁ -C₆ alkyl, cycloalkyl, aryl,arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl,pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, or thienylglycyloxymethyl. The most preferredester-forming radicals are those where R₃ is alkyl, particularly alkylof 1 to 10 carbons, (ie CH₃ --(CH₂)_(n) -- where n is 0-9), orphenyl-(CH₂)_(n) -- where n is 0-4.

When R₂ is referred to as being an amine, that includes the radical--NH₂ and mono- or dialkylate derivatives of this --NH₂ radical.Preferred alkylated amines are the mono- or disubstituted amines having1 to 6 carbons. When R₂ is referred to as being an amide, that includesall acylate derivatives of the NH₂ radical. The preferred amides arethose having 1 to 6 carbons.

Where there is an acid group, amides may be formed. The most preferredamides are those where --R₆ is hydrogen or alkyl of 1 to 6 carbon atoms.Particularly preferred is the diethylamide or dimethylamide.

Pharmaceutically acceptable salts of the instant compounds are intendedto be covered by this invention. These salts will be ones which areacceptable in their application to a pharmaceutical use. By that it ismeant that the salt will retain the biological activity of the parentcompound and the salt will not have untoward or deleterious effects inits application and use in treating diseases.

Pharmaceutically acceptable salts are prepared in a standard manner, ina suitable solvent. The parent compound in a suitable solvent is reactedwith an excess of an organic or inorganic acid, in the case of acidaddition salts, or an excess of organic or inorganic base in the casewhere R₄ is OH.

N-oxides may also be prepared by means of selected oxidizing agents.These oxides are useful as intermediates in preparing the compounds offormula I and have useful pharmaceutical activity in and of themselves.Hence one can administer the N-oxides of formula I to a subject who issusceptible to or is suffering from a disease related to or caused byLTB₄ or similar leukotrienes.

If by some combination of substituents, a chiral center is created oranother form of an isomeric center is created in a compound of thisinvention, all forms of such isomer(s) are intended to be coveredherein. These compounds may be used as a racemic mixture or theracemates may be separated and the individual enantiomer used alone.Olefins may have the cis or trans configuration (E or Z); either areuseful in the practice of this invention.

As leukotriene antagonists, these compounds can be used in treating avariety of disease assoicated with or attributing their origin or affectto leukotrienes, particularly LTB₄. Thus it is expected that thesecompounds can be used to treat allergic diseases such of a pulmonary andnon-pulmonary nature. For example these compounds will be useful inantigen-induced anaphylaxis; for treating asthma and allergic rhinitis;psoriasis, or irritable bowel disease; ocular diseases such as uveitis,and allergic conjunctivitis.

The preferred compounds are those where Z is O or S(O)_(q) ; m is 0-3; nis 0-2; R is alkoxy of 8 to 15 carbon atoms or unsubstituted orsubstituted pheny-C₁ to C₁₀ -aliphatic-O--; and R₁ is --(C₁ to C₅aliphatic)R₄ or --(C₁ to C₅ -aliphatic)CH₂ OR₈. The more preferredcompounds of this invention are those where R₁ is R₄ CH═CH-- and R₂ is--COR₅ or --NHSO₂ CF₃. Another set of preferred compounds are theanilines, those where R₂ is N(R₇)₂, particularly where R₇ is hydrogen. Athird set of preferred compounds are those where both R₂ and R₃ arehydrogen.

The most preferred compounds are:

1-fluoro-3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy[-6-pyridyl]propyl]benzene,lithium salt;

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene,lithium salt;

3-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene,lithium salt;

2-[2-thia-3-[2-(2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]ethyl]benzene,lithium salt;

1-fluoro-4-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene,lithium salt;

1-fluoro-4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene,lithium salt;

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]benzoicacid,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-[8-(4methoxyphenyl)octyloxy]-6-pyridyl]ethyl]benzoicacid,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid,

3-[1-dioxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid,

2-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, lithium salt

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6pyridyl]ethyl]-phenyl]trifluoromethanesulfonamide,

N-[3-[1-thia-2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]trifluoromethanesulfonamide,

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)6-pyridyl]ethyl]phenyl]-trifluoromethanesulfonamide,

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]-phenylsulfonamide,

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-phenyl]phenylsulfonamide,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]benzoicacid,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octan-1-yl]-6-pyridyl]ethyl]benzoicacid,

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid,

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoicacid,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoicacid,

3-[2-thia-3-[2-(2-carboxyethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl]-N,N,-dimethylbenzamide,lithium salt

3-[2-thia-3-[2-(E-2-carboxyethenyl)3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]propyl]-N,N-dimethylbenzamide,lithium salt,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-phenylbutyloxy]-6-pyridyl]propyl]benzoicacid,

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-phenyloctyloxy]-6-pyridyl]propyl]benzoicacid,

3-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoicacid,

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylaceticacid,

4-[2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid,

3-[2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid,

4-[2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylaceticacid,

3-[2-dioxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid,

5-[3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenyl]tetrazole

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,

5-carboxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)octyloxy)-6-pyridyl]ethyl]aniline,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyloctyloxy)-6-pyridyl]ethyl]aniline,lithium salt

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-fluorophenyl)octyloxy)-6-pyridyl]ethyl]aniline,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyl)octyloxy)-6-pyridyl]ethyl]aniline,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline,

3-[1-thia-2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]ethyl]aniline,lithium salt

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]ethyl]aniline,lithium salt

3-[1-dioxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]ethyl]aniline,lithium salt

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl]-N,N-dimethylaniline,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline,

3-[1-dioxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,

(E)-lithium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[2-phenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-lithium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(3,4-dichlorophenylthio)methyl]-2pyridinyl]-2-propenoate,

(E)-lithium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(4-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(4-fluorophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E) lithium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[2-chlorobenzylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2-methylphenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[3-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2-methoxyphenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2,4-dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2-bromophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]6-[(2-methylphenylthio)methyl]-2-pyridinyl]-2-propenoate.

Synthesis

There are several methods for preparing these compounds. One genericprocess comprises preparing a 6-(halomethyl)pyridyl adduct and thencondensing this fragment with the appropriate mercaptan or alcohol tomake compounds where Z is sulfur or oxygen. Usually, functional groupssuch as acid groups will be protected; any acid group may be derivatizedin some manner to render it unreactive. After the condensation reaction,protecting groups may be removed to provide the parent functionality,e.g. an acid. Further modification of these reactive groups can then becarried out, such as forming a salt, an amide, an ester or the like.Sulfonamides are prepared from the corresponding amines by literaturemethods. Tetrazoles are prepared from the corresponding acid halide,e.g., the acid chloride, by literature methods.

More specific illustrations of chemistry for making these compounds isprovided in the following reaction schemes. Scheme I outlines a meansfor making a substituted phenylalkyl tail which is R. ##STR3##

The starting alcohol, represented here as the 3-octyn-1-ol, iscommercially available (Lancaster Synthesis). To migrate the triple bondto the w-carbon, KH and 1,3-diaminopropane are combined and stirred to ahomogeneous mix. This can be done at ambient temperature or thereabouts.This mix is then cooled, preferably to about 0° C. or thereabouts,whereupon the alcohol is added. Stirring is then commenced at about roomtemperature for 15 to 20 hours or so. Water is added to quench thereaction and the product is recovered.

Protecting the alcohol is accomplished by forming a silyl etherillustrated here as the t-butyldiphenylsilyl ether. Other silyl etherscould be used. The alcohol is dissolved in a polar solvent, for exampledimethylformamide, and imidazole is added followed by the desiredsilane. All this is carried out under an inert atmosphere such as argon.Ambient temperature is acceptable for effecting the reaction.

Adding the phenyl group is done in a dry environment using an amine fora solvent and an inert atmosphere. To a flask containing a solvent suchas triethylamine under argon is added the silylether followed by ahalophenyl compound, eg. iodoanisole, a palladium catalyst (Ph₃ P)₂PdCl₂ and CuI, both of the latter in catalytic amounts. Heat is used toeffect the reaction, usually a temperature of up to about 50° C. will besufficient. Two or more hours, up to six but often about four at theelevated temperature will usually cause the reaction to go tocompletion.

The triple bond is then saturated, preferably by catalytichydrogenation. For example, the silyl ether can be dissolved in asaturated solvent such as an alcohol, a heavy metal catalyst added(Pd--C) and the mixture put under H₂ for a time sufficient to reduce thetriple bond. Stirring for 2 to 6 hours will usually effect the reaction.

Recovering the alcohol is done by treating the silyl ether with afluoride source such as tetrabutylammonium fluoride. Reactants arecombined at a mildly reduced temperature, eg. 0° C., then the reactionis allowed to run its course at ambient temperature or them about.Several hours may be needed for the reaction to go to completion.Product was recovered by extraction means.

Converting the alcohol to the iodo compound is accomplished using aphosphine, imidazole and I₂. In actual practice, this transformation isaccomplished by adding to a solution of alcohol under argon, a molarexcess of triphenylphosphine, for example, and a three-fold excess ofimidazole followed by iodine. Materials are combined at roomtemperature, but then the reaction pot may be heated to between 50°-70°C. for a brief period, 10 minutes to an hour to complete the reaction.Standard procedures are then used to recover and purify the product.

Scheme II illustrates an alternative process for making R groups.##STR4##

While the methoxyphenyl compound is illustrated here, this series ofsteps and reagents may be used to make othersubstituted-w-phenylaliphatic groups denoted by R. The startingmaterial, the benzaldehydes, are commercially available or can bereadily made by known methods.

To make the acid, first an alkylsilazide is added to an inert solventunder an inert atmosphere. Then the phosphonium salt is added. Thisaddition can be done at room temperature or thereabouts. After a briefperiod of mixing, this mixture is usually a suspension, the benzaldehydeis added slowly at about room temperature. A slight molar excess of thephosphonium salt is employed. After an additional brief period ofstirring at about room temperature, the reaction is quenched with water.The solution is acidified and the acid extracted with a suitable organicsolvent. Further separatory and purification procedures may be employedas desired.

The alcohol is made by reducing the acid using a reducing agent. Lithiumaluminum hydride or similar reducing agents may be employed, andconditions may be varied as needed to effect the reduction.

The tosylate is prepared in an inert solvent employing a base such aspyridine. Suitable conditions include carrying out the reaction at roomtemperature or thereabouts for a period of 1 to 5 hours. Other leavinggroups similar in function to the tosylate may be prepared and will beuseful as a means for forming the R moiety.

These procedures can be used to make the full spectrum of radicalsrepresented by R where it has a terminal phenyl group, including thesubstituted phenylaliphatic radicals.

Benzyl mercaptans, or analogous compounds where m is 1 or greater, arecommercially available or may be made by the process of Scheme III.##STR5##

Starting material, the haloalkylbenzoates, are commercially available orcan be made by methods known in the art. Thiourea is added to a solutionof haloalkylbenzoate at ambient temperature or thereabouts. Anyappropriate solvent may be used, acetone for example. A precipitate ofthe thiouronium salts should form under these conditions. Theprecipitate is collected and dissolved in water and the pH adjusted toabout 10.5 with a base, for example a solution of NaOH. Refluxing isthen commenced for between 1 and 4 hours. Product, as the free acid, isthen recovered by some other separatory and purification means.Esterification is then carried out by mixing the acid with an alcohol,bubbling HCl through the solution, and letting sit the resultingsolution for a time not more than several days; two days usually issufficient to effect the reaction.

Compounds of formula I where Z is oxygen can be made by the sequence ofsteps given in Scheme IV. ##STR6##

The starting material is available from Aldrich. It is treated with amild oxidizing agent such as MnO₂ to oxidize the 2-hydroxyethyl group tothe corresponding aldehyde. The R group is then formed. In this case anether is prepared under basic conditions using an a-halo intermediate. Atosylate made as per Scheme III, can also be used in this step.Introducing the acid function at position 2 is accomplished by means ofa triphenylphosphoranylidene reagent. The acetate form is illustratedhere but other similar reagents could be used. The N-oxide is thenformed by means of a peroxy acid. Trifluoroacetic anhydride is used tooxidize the 6-position methyl group. This hydroxymethyl group is thenconvened to the corresponding halide, (in the hydrohalide form) in thiscase the chloride, by means of thionyl chloride. An alkylhydroxybenzoate is then reacted with the 6-chloromethyl compound in thepresence of tetrabutylammonium iodide and a weak base. The resultingdiester can be hydrolyzed to the salt or, further, acidified to give thefree acid. An oxidant can be used to regenerate the N-oxide which canthen be treated with base to hydrolyze the esters. Esters can beconvened to salts, the free acids and other derivatives. Catalytichydrogenation can be used to reduce the double bond in the R₁ groupdescribed here.

Scheme V illustrates a method for making compounds where Z is a S and mis 0. ##STR7##

The starting hydrochloride is described in Scheme IV. Instead oftreating the hydrochloride with an alcohol, in this instance themercapto analog of the hydroxybenzoate described above is used. Theresulting thioether can be hydrolyzed to give the salt or treatedfurther to give the free acid from which other derivatives of thecarboxyl function can be prepared, including alcohols and aldehydes.Also, the double bond in the R₁ group can be reduced by catalytic meansusing a heavy metal catalyst and hydrogen.

Once the thioether is prepared, the sulfone and sulfoxide can beprepared by treating the thioether with an oxidizing agent, A peroxyacid or other oxidizing agent can be used.

A method for making compounds where R is alkyl or subsituted alkyl isgiven in Scheme VI. ##STR8##

In this Scheme, 2-hydroxypicolinic acid is converted to the alkyl esterusing the corresponding alcohol and an acid to catalyze the reaction.The hydroxyl group is then converted to the trifluoromethysulfonate bymeans of trifluormethanesulfonic anhydride and a base, e.g. pyridine.The lipid tail is attached using the appropriate alkyl catechol boronateunder palladium coupling conditions. For example, 1-iododecene andcatechol borane are reacted to form the alkyl catechol boronate. Thenthe alkylation reaction is effected using Pd(OAc)₂. The ester is reducedto the corresponding aldehyde with a hydride such as diisobutylaluminumhydride (DIBAL). A Wittig olefination is then carried out using, forexample, methyl(triphenylphosphoranylidene)acetate. The resultingpyridyl methyl acrylate is then oxidized to the N-oxide with anoxidizing agent such as 3-chloroperoxybenzoic acid. This oxide is thenrearranged to the 2-pyridone with trifluoroacetic anhydride. Atrifluoromethysulfonate is then formed using trifluormethanesulfonicanhydride and pyridine. Carbomethylation is then effected by means ofPd(OAc)₂, a simple alcohol, and carbon monoxide. Selectively reducingthe pyridyl-ester (using a hydride such as NaBH₄ in a low molecularweight alcohol) yields the 2-(hydroxymethyl)-pyridine. This compound istreated with thionyl chloride to form the 6-chloromethyl compound Thisintermediate is transformed to the ethers or thioether of formula I inthe same manner as is illustrated in Schemes IV-VI.

Pharmaceutical compositions of the present invention comprise apharmaceutical carrier or diluent and some amount of a compound of theformula (I). The compound may be present in an amount to effect aphysiological response, or it may be present in a lesser amount suchthat the user will need to take two or more units of the compositon toeffect the treatment intended. These compositions may be made up as asolid, liquid or in a gaseous form. Or one of these three forms may betransformed to another at the time of being administered such as when asolid is delivered by aerosol means, or when a liquid is delivered as aspray or aerosol.

The nature of the composition and the pharmaceutical carrier or diluentwill, of course, depend upon the intended route of administration, forexample parenterally, topically, orally or by inhalation.

For parenteral administration the pharmaceutical composition will be inthe form of a sterile injectable liquid such as an ampule or an aqueousor non-aqueous liquid suspension.

For topical administration the pharmaceutical composition will be in theform of a cream, ointment, liniment, lotion, pastes, and drops suitablefor administration to the eye, ear, or nose.

For oral administration the pharmaceutical composition will be in theform of a tablet, capsule, powder, pellet, atroche, lozenge, syrup,liquid, or emulsion.

When the pharmaceutical composition is employed in the form of asolution or suspension, examples of appropriate pharmaceutical carriersor diluents include: for aqueous systems, water; for non-aqueoussystems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil,peanut oil, sesame oil, liquid parafins and mixtures thereof with water;for solid systems, lactose, kaolin and mannitol; and for aerosolsystems, dichlorodifluoromethane, chlorotrifluoroethane and compressedcarbon dioxide. Also, in addition to the pharmaceutical carrier ordiluent, the instant compositions may include other ingredients such asstabilizers, antioxidants, preservatives, lubricants, suspending agents,viscosity modifiers and the like, provided that the additionalingredients do not have a detrimental effect on the therapeutic actionof the instant compositions.

The pharmaceutical preparations thus described are made following theconventional techniques of the pharmaceutical chemist as appropriate tothe desired end product.

Formulations for treating psoriasis can take the form of oral or topicalpreparations. Topically applied formulations are preferred. Ointments,creams, liniments, lotions, pastes and similar preparations are examplesof preferred topical formulations. Aerosols may also be used. Thesedosage forms will contain between 0.01 and 5 percent by weight of theactive ingredient.

Usually a compound of formula I is administered, that is applied, to asubject in a composition comprising a nontoxic amount sufficient toproduce an inhibition of the symptoms of a disease state. Whenadministered orally, the dosage of the composition is selected from therange of from 50 mg to 1000 mg of active ingredient for eachadministration. For convenience, equal doses will be administered 1 to 5times daily with the daily dosage regimen being selected from about 50mg to about 5000 mg. When a topical formulation is used, the amountapplied will depend on the size of the affected area and the severityand progress of the disease, ie. psoriasis. Included within the scope ofthis disclosure is the method of treating a disease mediated by LTB₄which comprises administering to a subject a therapeutically effectiveamount of a compound of formula I, preferably in the form of apharmaceutical composition. For example, inhibiting the inflammatoryresponse resulting from psoriasis by administration of an effectiveamount of a compound of formula I is included within the scope of thisdisclosure. The administration may be carried out in dosage units atsuitable intervals or in single doses as needed. Usually this methodwill be practiced when relief of symptoms is specifically required.However, the method is also usefully carried out as continuous orprophylactic treatment. It is within the skill of the art to determineby routine experimentation the effective dosage to be administered fromthe dose range set forth above, taking into consideration such factorsas the degree of severity of the condition or disease being treated, andso forth.

Pharmaceutical compositions and their method of use also include thecombination of a compound of formula I with H₁ blockers where thecombination contains sufficient amounts of both compounds to treatantigen-induced respiratory anaphylaxis or similar allergic reaction.Representative H₁ blockers useful here include: cromolyn sodium,compounds from the ethanolamines class (diphenhydramine),ethylenediamines (pyrilamine), the alkylamine class (chlorpheniramine),the piperazine class (chlorcyclizine), and the phenothiazine class(promethazine). H₁ blockers such as2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid-3-yl)methyl]-4-pyrimidoneare particularly useful in this invention.

Bioassays

The specificity of the antagonist activity of a number of the compoundsof this invention is demonstrated by relatively low levels of antagonismtoward agonists such as potassium chloride, carbachol, histamine andPGF₂.

The receptor binding affinity of the compounds used in the method ofthis invention is measured by the ability of the compounds to bind to [³H]-LTB₄ binding sites on human U937 cell membranes. The LTB₄ antagonistactivity of the compounds used in the method of this invention ismeasured by their ability to antagonize in a dose dependent manner theLTB₄ elicited calcium transient measured with fura-2, the fluorescentcalcium probe. The methods employed were as follows:

U-937 Cell Culture Conditions

U-937 cells were obtained from Dr. John Bomalaski (Medical College ofPA) and Dr. John Lee (SmithKline Beecham Corp., Dept. of Immunology) andgrown in RPMI-1640 medium supplemented with 10% (v/v) heat inactivatedfetal calf serum, in a humidified environment of 5% CO₂, 95% air at 37°C. Cells were grown both in T-flasks and in Spinner culture. Fordifferentiation of the U937 cells with DMSO to macrophage-like cells,the cells were seeded at a concentration of 1×10⁵ cells/ml in the abovemedium with 1.3% DMSO and the incubation continued for 4 days. The cellswere generally at a density of 0.75-1.25×10⁶ cells/ml and were harvestedby centrifugation at 800×g for 10 min.

Preparation of U-937 Cell Membrane Enriched Fraction

Harvested U-937 cells were washed with 50 mM Tris-HCl, pH 7.4 at 25° C.containing 1 mM EDTA (buffet A). Cells were resuspended in buffer A at aconcentration of 5×10⁷ cells/ml and disrupted by nitrogen cavitationwith a Parr bomb at 750 psi for 10 min at 0° C. The broken cellpreparation was centrifuged at 1,000×g for 10 min. The supernatant wascentrifuged at 50,000×g for 30 min. The pellet was washed twice withbuffer A. The pellet was resuspended at about 3 mg membrane protein/mlwith 50 mM Tris-HCl, pH 7.4 at 25° C. and aliquots were rapidly frozenand stored at -70° C.

Binding of [³ H]-LTB₄ to U-937 Membrane Receptors

[³ H]-LTB₄ binding assays were performed at 25° C., in 50 mM Tris-HCl(pH 7.5) buffer containing 10 mM CaCl₂, 10 mM MgCl₂, [³ H]-LTB₄, U937cell membrane protein (standard conditions) in the presence or absenceof varying concentrations of LTB₄, or test compounds. Each experimentalpoint represents the means of triplicate determinations. Total andnon-specific binding of [³ H]-LTB₄ were determined in the absence orpresence of 2 mM of unlabeled LTB₄, respectively. Specific binding wascalculated as the difference between total and non-specific binding. Theradioligand competition experiments were performed, under standardconditions, using approximately 0.2 nM [³ H]-LTB₄, 20-40 mg of U937 cellmembrane protein, increasing concentrations of LTB₄ (0.1 mM to 10 mM) orother competing ligands (0.1 mM to 30 mM) in a reaction volume of 0.2 mland incubated for 30 minutes at 25° C. The unbound radioligand andcompeting drugs were separated from the membrane bound ligand by avacuum filtration technique. The membrane bound radioactivity on thefilters was determined by liquid scintillation spectrometry.

Saturation binding experiments for U937 cells were performed, understandard conditions, using approximately 15-50 mg of U-937 membraneprotein and increasing concentrations of [³ H]-LTB₄ (0.02-2.0 nM) in areaction volume of 0.2 ml and incubation at 22° C., for 30 minutes. LTB₄(2 mM) was included in a separate set of incubation tubes to determinenon-specific binding. The data from the saturation binding experimentswas subjected to computer assisted non-linear least square curve fittinganalysis and further analyzed by the method of Scatchard.

Loading Differentiated U-937 Cells with Fura-2

Harvested cells were resuspended at 2×10⁶ cells/ml in Krebs RingerHensilet buffer containing 0.1% BSA (RIA grade), 1.1 mM MgSO₄, 1.0 mMCaCl₂ and 5 mM HEPES (pH 7.4, buffer B). The diacetomethoxy ester offura-2 (fura-2/AM) was added to a final concentration of 2 mM and cellsincubated in the dark for 30 minutes at 37° C. The cells werecentrifuged at 800×g for 10 minutes and resuspended at 2×10⁶ cells/ml infresh buffer B and incubated at 37° C. for 20 minutes to allow forcomplete hydrolysis of entrapped ester. The cells were centrifuged at800×g for 10 minutes and resuspended in cold fresh buffer B at 5×10⁶cells/ml. Cells were maintained on ice in the dark until used forfluorescent measurements.

Fluorescent Measurements--Calcium Mobilization

The fluorescence of fura-2-containing U937 cells was measured with afluorometer designed by the Johnson Foundation BiomedicalInstrumentation Group. A fluorometer was equipped with temperaturecontrol and a magnetic stirrer under the cuvette holder. The wavelengths are set at 339 nm for excitation and 499 nm for emission. Allexperiments were performed at 37° C. with constant mixing.

U-937 cells were diluted with fresh buffer (B) to a concentration of1×10⁶ cells/ml and maintained in the dark on ice. Aliquots (2 ml) of thecell suspension were put into 4 ml cuvettes and the temperature broughtup to 37° C., (maintained in 37° C., water bath for 10 min). Cuvetteswere transferred to the fluorometer and fluorescence measured for aboutone minute before addition of stimulants or antagonists and followed forabout 2 minutes post stimulus. Agonists and antagonists were added as 2ml aliquots.

Antagonists were added first to the cells in the fluorometer in order todetect potential agonist activity. Then after about one minute 10 nMLTB₄ (a near maximal effective concentration) was added and the maximalCa²⁺ mobilization [Ca²⁺ ]_(i) was calculated using the followingformula: ##EQU1## F was the maximum relative fluorescence measurement ofthe sample. Fmax was determined by lysing the cells with 10 ml of 10%Triton X-100 (final Concentration 0.02%). After Fmax was determined 67ml of 100 mM EDTA solution (pH 10) was added to totally chelate the Ca²⁺and quench the fura-2 signal and obtain the Fmin. The [Ca²⁺ ]_(i) levelfor 10 nM LTB₄ in the absence of an antagonist was 100% and basal [Ca²⁺]_(i) was 0%. The IC₅₀ concentration is the concentration of antagonistwhich blocks 50% of the 10 nM LTB₄ induced [Ca²⁺ ]_(i) mobilization. TheEC₅₀ for LTB₄ induced increase in [Ca²⁺ ]_(i) mobilization was theconcentration for half maximal increase. The K_(i) for calciummobilization was determined using the formula: ##EQU2## With theexperiments described, the LTB₄ concentration was 10 nM and the EC₅₀ was2 nM.

SPECIFIC EMBODIMENTS

The following examples are given to illustrate how to make and use thecompounds of this invention. These Examples are just that, examples, andare not intended to circumscribe or otherwise limit the scope of thisinvention. Reference is made to the claims for defining what is reservedto the inventors by this document.

EXAMPLE 1 8-(4-Methoxyphenyl)octan-1-(4-toluenesulfonate) 1(a)7-Octyn-1-ol

35% KH in mineral oil (27 g, 240 mmol) under an argon atmosphere waswashed with hexane and treated dropwise with 1,3-diaminopropane. Themixture was stirred at room temperature until it became homogeneous. Theflask was cooled to 0∞C and 3-octyn-1-ol (10 g, 79 mmol, LancasterSynthesis) was slowly added. The reaction was then stirred at roomtemperature for 18 hours. The reaction was quenched with H₂ O (50 mL)and the product was extracted into ether. The organic layer was washedwith 10% HCl (3×15 mL) and brine and dried (MgSO₄). Evaporation gave thetitle product which was used without further purification: ¹ H NMR (90MHz, CDCl₃) d 3.65 (t, J=5 Hz, 2H, OCH₂), 2.23 (m, 2H, CH₂), 2.0 (m, 1H,acetylenic), 1.7-1.2 (m, 8H, (CH₂)₄); IR (neat) u_(max) 3350, 2930, 2125cm⁻¹.

1(b) 7Octyn-1-t-butyldiphenylsilyl ether

7-Octyn-1-ol (3.8 g) was dissolved in dimethylformamide (10 mL) andtreated with t-butylchlorodiphenylsilane (10.2 mL, 33 mmol) andimidazole (3.65 g, 45 mmol) at 0∞C. The reaction was stirred at 0∞C for10 minutes and at room temperature for 3 hours. Water was added and theproduct was extracted into ethyl acetate. The ethyl acetate extract waswashed with H₂ O and brine and dried (Na₂ SO₄). The solvent wasevaporated and the residue purified by flash column chromatography(silica, hexanes) to give a yellow oil: ¹ H NMR (250 MHz, CDCl₃)d7.7 (d,4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, OCH₂), 2.23 (m, 2H, CH₂),1.97 (t, 1H, acetylenic), 1.6-1.3 (m, 8H, (CH₂)₄), 1.05 (s, 9H,t-butyl); IR (film)u_(max) 3321, 2940, 2125 cm⁻¹.

1(c) 8-(4-Methoxyphenyl)-7-octyn-1-t-butyldiphenylsilyl ether

To a flame-dried flask under an argon atmosphere was added 4-iodoanisole(5.34 g, 22 mmol) in triethylamine (50 mL) followed by the addition of7-octyn-1-t-butyldiphenylsilyl ether (9.84 g, 27 mmol), (Ph₃ P)₂ PdCl₂(350 mg, 0.44 mmol), and CuI (200 mg, 0.88 mmol). The resulting mixturewas heated at 50∞C for 4 hours. Upon cooling to room temperature thereaction mixture was filtered and the solvent evaporated. The residuewas partitioned between ethyl acetate and H₂ O and the organic layer wascollected and washed with brine and dried (Na₂ SO₄). The solvent wasevaporated and the residue was purified by flash column chromatography(silica, 1% ethyl acetate in hexanes) to give an oil: ¹ H NMR (250 MHz,CDCl₃) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8(d, 2H, aryl), 3.8 (s, 3H, OCH₃), 3.7 (t, 2H, OCH₂), 2.4 (t, 2H, CH₂),1.7-1.3 (m, 8H, (CH₂)₄), 1.05 (s, 9H, t-butyl).

1(d) 8-(4-Methoxyphenyl)octan-1-t-butyldiphenylsilyl ether

To 8-(4-methoxyphenyl)-7-octyn-1-t-butyldiphenylsilyl ether (2.16 g, 4.6mmol) in ethanol (10 mL) and ethyl acetate (10 mL) was added 5% Pd/C(100 mg). The mixture was subjected to 75 psi of H₂ for 4 hours. Thereaction was filtered through Celite and the solvent evaporated to givean oil: ¹ H NMR (250 MHz, CDCl₃) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl),7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH₃), 3.6 (t, 2H,OCH₂), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH₂)₆), 1.0 (s, 9H,t-butyl).

1(e) 8-(4-Methoxyphenyl)octan-1-ol

8-(4-Methoxyphenyl)octan-1-t-butyldiphenylsilyl ether (2.18 g, 4.6 mmol)in tetrahydrofuran (20 mL) was cooled to 0∞C and treated withtetrabutylammonium fluoride (14 mL, 14 mmol, 1M in tetrahydrofuran). Thecooling bath was removed and the reaction was stirred at roomtemperature for 24 hours. The reaction was diluted with ethyl acetateand was washed with H₂ O and brine and dried (Na₂ SO₄). The solvent wasevaporated and the residue was purified by flash column chromatography(silica, 0-20% ethyl acetate in hexanes) to give a white solid: ¹ H NMR(250 MHz, CDCl₃) δ 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H,OCH₃), 3.68 (t, 2H, OCH₂), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H,(CH₂)₆).

1(f) 8-(4-Methoxyphenyl)octan-1-(4-toluenesulfonate)

6-(4-Methoxyphenyl)octan-1-ol (5.91 g, 25 mmol was dissolved in dry CH₂Cl₂ (100 mL) under an argon atmosphere and cooled to 0∞C. To this wasadded pyridine (2.5 mL, 30 mmol) and 4-toluenesulfonyl chloride (5.48,28 mmol). The reaction was stirred at 0∞C for 20 minutes and at roomtemperature for 24 hours. The reaction solution was washed with H₂ O andbrine and dried (Na₂ SO₄). The solvent was evaporated and the residuepurified by flash column chromatography (silica, 0-10% ethyl acetate inhexanes) to give a white solid: ¹ H NMR (250 MHz, CDCl₃) δ 7.79 (d, 2H,aryl), 7.35 (d, 2H, aryl), 7.09 (d, 2H, aryl), 6.82 (d, 2H, aryl), 4.04(s, 2H, OCH₂), 3.8 (s, 3H, OCH₃), 2.55 (t, 2H, benzylic), 2.46 (s, 3H,CH₃), 1.75-1.15 (m, 12H, (CH₂)₆).

EXAMPLE 2 6-(4-Methoxyphenyl)hexan-1-(4-toluenesulfonate) 2(a)5Hexyn-1-t-butyldiphenylsilyl ether

5-Hexyn-1-ol (38, 30 mmol, Aldrich) was dissolved in dimethylformamide(10 mL) and treated with t-butylchlorodiphenylsilane (10.2 mL, 33 mmol)and imidazole (3.65 g, 45 mmol) at 0∞C. The reaction was stirred at 0∞Cfor 10 minutes and at room temperature for 3 hours. Water was added andthe product was extracted into ethyl acetate. The ethyl acetate extractwas washed with H₂ O and brine and dried (Na₂ SO₄). The solvent wasevaporated and the residue purified by flash column chromatography(silica, hexanes) to give a yellow oil: ¹ H NMR (250 MHz, CDCl₃) δ 7.7(d, 4H, aryl), 7.4 (m, 6H, aryl), 3.65 (t, 2H, OCH₂), 2.2 (m, 2H, CH₂),1.9 (t, 1H, acetylenic), 1.7 (m, 4H, CH₂ --CH₂), 1.05 (s, 9H, t-butyl).

2(b) 6-(4-Methoxyphenyl)-5-hexyn-1-t-butyldiphenylsilyl ether

To a flame-dried flask under an argon atmosphere was added 4-iodoanisole(5.34 g, 22 mmol) in triethylamine (50 mL) followed by the addition of5-hexyn-1-t-butyldiphenylsilyl ether (8.83 g, 27 mmol), (Ph₃ P)₂ PdCl₂(350 mg, 0.44 mmol), and CuI (200 mg, 0.88 mmol). The resulting mixturewas heated at 50∞C for 4 hours. Upon cooling to room temperature thereaction mixture was filtered and the solvent evaporated. The residuewas partitioned between ethyl acetate and H₂ O and the organic layer wascollected and washed with brine and dried (Na₂ SO₄). The solvent wasevaporated and the residue was purified by flash column chromatography(silica, 1% ethyl acetate in hexanes) to give an oil: ¹ H NMR (250 MHz,CDCl₃) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8(d, 2H, aryl), 3.8 (s, 3H, OCH₃), 3.7 (t, 2H, OCH₂ ), 2.4 (t, 2H, CH₂),1.7 (m, 4H, CH₂ --CH₂), 1.05 (s, 9H, t-butyl).

2(c) 6-(4-Methoxyphenyl)hexan-1-t-butyldiphenylsilyl ether

To 6-(4-methoxyphenyl)-5-hexyn-1-t-butyldiphenylsilyl ether (2.0 g, 4.6mmol) in ethanol (10 mL) and ethylacetate (10 mL) was added 5% Pd/C (100mg). The mixture was subjected to 75 psi of H₂ for 4 hours. The reactionwas filtered through Celite and the solvent evaporated to give an oil: ¹H NMR (250 MHz, CDCl₃) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d,2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH₃), 3.6 (t, 2H, OCH₂), 2.5(t, 2H, benzylic), 1.55 (m, 4H, CH₂ --CH₂), 1.3 (m, 4H, CH₂ --CH₂), 1.0(s, 9H, t-butyl).

2(e) 6-(4-Methoxyphenyl)hexan-1-ol

6-(4-Methoxyphenyl)hexan-1-t-butyldiphenylsilyl ether (2.0 g, 4.6 mmol)in tetrahydrofuran (20 mL) was cooled to 0∞C and treated withtetrabutylammonium fluoride (14 mL, 14 mmol, 1M in tetrahydrofuran). Thecooling bath was removed and the reaction was stirred at roomtemperature for 24 hours. The reaction was diluted with ethyl acetateand was washed with H₂ O and brine and dried (Na₂ SO₄). The solvent wasevaporated and the residue was purified by flash column chromatography(silica, 0-20% ethyl acetate in hexanes) to give a white solid: ¹ H NMR(250 MHz, CDCl₃) ι 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H,OCH₃), 3.65 (t, 2H, OCH₂), 2.55 (t, 2H, benzylic), 1.6 (m, 4H, CH₂--CH₂), 1.4 (m, 4H, CH₂ --CH₂).

2(f) 6-(4-Methoxyphenyl)hexan-1-(4-toluenesulfonate)

6-(4-Methoxyphenyl)hexan-1-ol (5.36 g, 25 mmol) was dissolved in dry CH₂Cl₂ (100 mL) under an argon atmosphere and cooled to 0∞C. To this wasadded pyridine (2.5 mL, 30 mmol) and 4-toluenesulfonyl chloride (5.4 g,28 mmol). The reaction was stirred at 0∞C for 20 minutes and at roomtemperature for 24 hours. The reaction solution was washed with H₂ O andbrine and dried (Na₂ SO₄). The solvent was evaporated and the residuepurified by flash column chromatography (silica, 0-10% ethyl acetate inhexanes) to give a white solid: ¹ H NMR (250 MHz, CDCl₃) δ 1.6-1.3 (m,8H, (CH₂)₄), 2.4 (s, 3H, CH₃), 2.5 (t, 2H, benzylic), 3.8 (s, 3H, OCH₃),4.0 (t, 2H, OCH₂), 6.80 (d, 2H, aryl), 7.0 (d, 2H, aryl), 7.3 (d, 2H,aryl), 7.8 (d, 2H, aryl).

EXAMPLE 3 E-6-(4-methoxyphenyl)-1-(4-toluenesulfonate)-5-hexene 3(a)E-4-Methoxyphenyl-5-hexenoic acid

To a freshly prepared solution of lithium hexamethyldisilazide (64 mmol)in tetrahydrofuran (30 mL), under an argon atmosphere, was added asuspension of (4-carboxybutyl)triphenylphosphonium bromide (17.6 g, 30mmol) in tetrahydrofuran (45 mL) at room temperature. The reaction wasstirred for 15 minutes during which time the orange-red color of theylide developed. A solution of 4-anisaldehyde (4.58 g, 30 mmol) intetrahydrofuran (30 mL) was added dropwise and stirring was continuedfor an additional 20 minutes. The reaction was quenched with H₂ O (50mL) and diluted with ether (30 mL). The aqueous layer was acidified topH 1.0 with 3N HCl and the product was extracted into ethyl acetate(3×50 mL). The combined organic layers were dried (MgSO₄) and theproduct was purified by flash column chromatography (silica, 1% methanolin CH₂ Cl₂) to yield the E-olefin as a solid: ¹ H NMR (200 MHz, CDCl₃) δ7.3 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.3 (d, 1H, olefin), 6.0 (m, 1H,olefin), 3.8 (s, 3H, OCH₃), 2.3 (m, 4H, allylic CH₂ and CH₂ CO₂), 1.8(q, 2H, CH₂).

3(b) E-4-Methoxyphenyl-5-hexen-1-ol

E-4-Methoxyphenyl-5-hexenoic acid (1.1 g, 5.0 mmol) in dry ether (10 mL)was slowly added to a suspension of LiAlH₄ (240 mg, 6.0 mmol) in ether(10 mL) under an argon atmosphere. The reaction mixture was refluxed for45 minutes. Upon cooling to room temperature the reaction was quenchedwith H₂ O (10 mL) followed by 6N H₂ SO₄ (7 mL). Ethyl acetate (20 mL)was added and the organic layer was separated and dried (MgSO4);evaporation gave a white crystalline solid: mp. 65-66∞C; ¹ H NMR (200MHz, CDCl₃) δ 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.3 (d, 1H, olefin),6.1 (m, 1H, olefin), 3.8 (s, 3H, OCH₃), 3.6 (t, 2H, OCH₂), 2.2 (q, 2H,allylic), 1.5 (m, 4H, CH₂ --CH₂); Anal. Calcd. for C₁₃ H₁₈ O₂, C, 75.65;H, 8.80, found: C, 75.45; H, 8.95; MS (CI): 207 (M+H).

3(c) E-6-(4-methoxyphenyl)-1-(4-toluenesulfonate)-5-hexene

E-4-Methoxyphenyl-5-hexen-1-ol (1.6 g, 7.0 mmol) was dissolved in dryCH₂ Cl₂ (50 mL) under an argon atmosphere and treated with4-toluenesulfonyl chloride (7.0 g, 36 mmol) and pyridine (3 mL). Thereaction solution was stirred at room temperature for 3.5 hours. Water(40 mL) was added to the reaction and the organic layer was separatedand dried (MgSO₄). The product was purified by flash columnchromatography (silica, 10% ethyl acetate in hexane) to give an oil: ¹ HNMR (200 MHz, CDCl₃) δ 7.8 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.2 (d, 2H,aryl), 6.8 (d, 2H, aryl), 6.2 (d, 1H, olefin), 6.0 (m, 1H, olefin), 4.1(t, 2H, OCH₂), 3.8 (s, 3H, OCH₃), 2.4 (s, 3H, CH₃), 2.1 (q, 2H, allylic), 1.6 (m, 4H, CH₂ --CH₂); MS (CI): 361 (M+H).

EXAMPLE 4 1-Iodo-8-(4-methoxyphenyl)octane 4(a) 7-Octyn-1-ol

Potassium hydride, (35%) in mineral oil (27 g, 240 mmol) under an argonatmosphere was washed with hexane and treated dropwise with1,3-diaminopropane. The mixture was stirred at room temperature until itbecame homogeneous. The flask was cooled to 0° C. and 3-octyn-1-ol (10g, 79 mmol, Lancaster Synthesis) was slowly added. The reaction was thenstirred at room temperature for 18 hours. The reaction was quenched withH₂ O (50 mL) and the product was extracted into ether. The organic layerwas washed with 10% HCl and brine and dried (MgSO₄). Evaporation gavethe captioned product as a colorless oil which was used without furtherpurification: ¹ H NMR (90 MHz, CDCl₃) δ 3.65 (t, J=5Hz, 2H, O--CH₂),2.23 (m, 2H, CH₂), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH₂)₄); IR(neat) n_(max) 3350, 2930, 2125 cm⁻¹.

4(b) 7-Octyn-1-tbutyldiphenylsilyl ether

To a cooled (0° C.) solution of 7-octyn-1-ol (9.3 g, 73.7 mmol) indimethylformamide (DMF) (70 mL) under an argon atmosphere was addedimidazole (7.5 g, 110 mmol) followed by the dropwise addition oft-butylchlorodiphenylsilane (21 mL, 81 mmol). The reaction was thenstirred at room temperature for 2 hours. The reaction solution wasdiluted with Et₂ O and washed with H₂ O and brine and dried (MgSO₄).Purification by flash column chromatography (silica, 3% EtOAc in hexane) provided the product as a colorless oil: ¹ H NMR (250 MHz, CDCl₃) δ7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, O--CH₂), 2.23 (m, 2H,CH₂), 1.97 (t, 1H, acetylenic), 1.6-1.3 (m, 8H, (CH₂)₄), 1.05 (s, 9H,t-butyl); IR (film) n_(max) 3321, 2940, 2125 cm⁻¹.

4(c) 8-(4-Methoxyphenyl)-7-octyn-1-t-butyldiphenylsilyl ether

To a flame dried flask containing triethylamine (140 mL) under an argonatmosphere was added 4-iodoanisole (13.3 g, 56.9 mmol),7-octyn-1-t-butyldiphenylsilyl ether (24.9 g, 68.3 mmol), (Ph₃ P)₂ PdCl₂catalyst (793 mg, 1.13 mmol), and CuI (431 mg, 2.27 mmol). The resultingmixture was heated at 50° C. for 4 hours. Upon cooling to roomtemperature the reaction mixture was filtered, the solids were washedwith Et₂ O and the solvent was evaporated. The residue was diluted withEt₂ O and washed with 5% HCl, H₂ O, NaHCO₃, and brine and dried (MgSO₄).Purification by flash column chromatography (silica, 2% EtOAc in hexane)gave the product as an orange oil: ¹ H NMR (250 MHz, CDCl₃) δ 7.7 (d,4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8(s, 3H, OCH₃), 3.7 (t, 2H, O--CH₂), 2.4 (t, 2H, CH₂), 1.7-1.3 (m, 8H,(CH₂)₄), 1.05 (s, 9H, t-butyl).

4(d) 8-(4-Methoxyphenyl)octan-1-t-butyldiphenylsilyl ether

8-(4-Methoxyphenyl)-7-octyn-1-t-butyldiphenylsilyl ether (30 g, 63.7mmol) was dissolved in EtOH (125 mL) and EtOAc (125 mL) and treated with5% Pd--C catalyst (3 g). The reaction was vigorously stirred under an H₂atmosphere (balloon pressure) for 4 hours. The reaction mixture wasfiltered through a pad of Celite and the solvent was evaporated. Theresulting pale yellow oil was pure by nmr analysis and was used directlyfor the next step: ¹ H NMR (250 MHz, CDCl₃) δ 7.7 (d, 4H, aryl), 7.4 (m,6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH₃), 3.6(t, 2H, O--CH₂), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH₂)₆), 1.0(s, 9H, t-butyl).

4(e) 8-(4-Methoxyphenyl)octan-1-ol

To a cooled (0° C.) solution of8-(4-methoxyphenyl)octan-1-t-butyldiphenylsilyl ether (63 mmol) wasadded tetrabutylammonium fluoride (70 mL, 70 mmol; 1M solution in THF).The cooling bath was removed and the reaction was stirred at roomtemperature for 4.5 hours. The solvent was evaporated and the residuewas dissolved in Et₂ O. This was washed with H₂ O, 5% HCl, NaHCO₃, andbrine and dried (MgSO₄). Purification by flash column chromatography(silica, 30% EtOAc in hexane) gave the product as a colorless solid: ¹ HNMR (250 MHz, CDCl₃) δ 7.15 (d, J=8.6 Hz, 2H, aryl), 6.86 (d, J=8.6 Hz,2H, aryl), 3.85 (s, 3H, OCH₃), 3.68 (t, J=6.5 Hz, 2H, O--CH₂), 2.62 (t,J=7.6 Hz, 2H, benzylic), 1.75-1.3 (m, 12H, (CH₂)₆); MS (CI): 254.2(M+NH₄); mp 47°-49° C.

4(f) 1-Iodo-8-(4-methoxyphenyl)octane

To a stirred solution of 8-(4-methoxyphenyl)octan-1-ol (12.3 g, 52 mmol)in dry toluene (200 mL) under an argon atmosphere was addedtriphenylphosphine (17.8 g, 67.6 mmol) and imidazole (10.6 g, 156 mmol).After the imidazole had dissolved, 12 (17.1 g, 67.6 mmol) was added. Thereaction was then heated at 65° C. for 30 minutes. Upon cooling to roomtemperature the reaction was concentrated to 1/4 volume. The remainingsolution was diluted with Et₂ O and washed with H₂ O and brine and dried(MgSO₄). The solvent was removed and the resulting residue was dissolvedin CH₂ Cl₂ and applied to a flash chromatography column (silica).Elution with 2% EtOAc in hexane provided the product as a colorless oil(slight contamination with triphenylphosphine): ¹ H NMR (250 MHz, CDCl₃)δ 7.08 (d, J=8.6 Hz, 2H, aryl), 6.82 (d, J=8.6 Hz, 2H, aryl), 3.78 (s,3H, OCH₃), 3.17 (t, J=7.4 Hz, 2H, I---CH₂), 2.54 (t, J=7.6 Hz, 2H,benzylic), 1.85 (m, 2H, CH₂), 1.60 (m, 2H, CH₂), 1.31 (m, 8H,aliphatic); MS (CI): 364.2 (M+NH₄).

EXAMPLE 53-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt 1(a) 3-Hydroxy-6-methyl-2-pyridine carboxaldehyde

2,6-Lutidine-a²,3-diol (1.0 g, 7.18 mmol, Aldrich) was suspended in dryCH₂ Cl₂ (40 mL) and treated with MnO₂ (6.1 g, 70 mmol). The reaction wasstirred at room temperature for 6 hours. The reaction mixture wasfiltered through a pad of Celite and the solvent was removed in vacuo.The aldehyde was used directly in the next step without furtherpurification: ¹ H NMR (250 MHz, CDCl₃): δ 10.65 (s, 1H, OH), 10.30 (s,1H, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 2.55 (s, 3H, CH₃).

5(b) 3-Dodecyloxy-6-methyl-2-pyridine carboxaldehyde

3-Hydroxy-6-methyl-2-pyridine carboxaldehye obtained above was dissolvedin dry dimethylformamide (10 mL) and treated with 1-iodododecane (2.1mL, 8.62 mmol) and anhydrous K₂ CO₃ (3.0 g, 21.7 mmol) under an argonatmosphere. The reaction was heated at 90° C. for 1 h with vigorousstirring. Upon cooling to room temperature the reaction mixture waspoured into ethyl acetate (100 mL); the ethyl acetate solution waswashed with H₂ O (3×20 mL) and brine and dried (MgSO₄). The solvent wasremoved under reduced pressure and the crude product was used directlyin the next step without further purification: ¹ H NMR (250 MHz, CDCl₃):δ 10.40 (s, 1H, CHO), 7.30 (m, 2H, 4-pyridyl, 5- pyridyl), 4.07 (t,J=6.5 Hz, 2H, OCH₂), 2.6 (s, 3H, CH₃), 1.85-0.89 (m, 23H, aliphatic).

5(c) 2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine

3-Dodecyloxy-6-methyl-2-pyridine carboxaldehyde obtained above wasdissolved in dry toluene (12 mL) under an argon atmosphere and treatedwith methyl (triphenylphosphoranylidene)acetate (5.0 g, 15 mmol). Thereaction was heated for 1 hour at 50∞C. Upon cooling to room temperaturethe reaction was diluted with ethyl acetate (10 mL) and washed with H₂ O(2×20 mL) and brine and dried (MgSO₄). Purification by flash columnchromatography (silica, 7.5% ethyl acetate in petroleum ether) gave acolorless solid: ¹ H NMR (250 MHz, CDCl₃): δ 8.07 (d, J=15.7 Hz, 1H,olefin), 7.10 (m, 2H, 4-pyridyl, 5-pyridyl), 7.05 (d, J=15.7 Hz, 1H,olefin), 3.98 (t, J=6 Hz, 2H, OCH₂), 3.80 (s, 3H, CO₂ CH₃), 2.49 (s, 3H,CH₃), 1.88-0.85 (m, 23H, aliphatic).

5(d) 2-(-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine N-oxide

2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine (2.15 g, 5.95mmol) was dissolved in dry CH₂ Cl₂ (20 mL) and cooled to 0∞C; 85%m-chloroperoxybenzoic acid (1.45 g, 7.14 mmol) was added and thereaction was stirred at 0∞C for 30 minutes and at room temperature for16 hours. The reaction solution was poured into sainted aqueous NaHCO₃(20 mL). The aqueous phase was extracted with CH₂ Cl₂ (3×20 mL) and thecombined CH₂ Cl₂ extracts were washed with H₂ O (20 mL) and brine anddried (MgSO₄). The crude pale yellow solid was used directly in the nextstep without further purification: ¹ H NMR (250 MHz, CDCl₃): δ 8.23 (d,J=16.2 Hz, 1H, olefin), 7.58 (d, J=16.2 Hz, 1H, olefin), 7.13 (d, J=8.8Hz, 1H, 5- pyridyl), 6.79 (d, J=8.8 Hz, 1H, 4-pyridyl), 4.06 (t, J=6.6Hz, 2H, OCH₂), 3.81 (s, 3H, CO₂ CH₃), 2.45 (s, 3H, CH₃), 1.92-0.85 (m,23H, aliphatic); MS (CI): 378.2 (M+H).

5(e) 2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(hydroxymethyl)pyridine

2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine N-oxideobtained above was suspended in dry dimethylformamide (20 mL) and cooledto 0∞C under an argon atmosphere. To this was slowly addedtrifluoroacetic anhydride (8.5 mL, 60.2 mmol). The reaction was stirredat 0∞C for 10 minutes and then at room temperature for 16 hours; thinlayer chromatography indicated that two reaction products were present(alcohol and trifluoroacetate). The reaction solution was slowly addedto a cooled (0∞C) saturated aqueous Na₂ CO₃ solution (100 mL). Theaqueous solution was extracted with ethyl acetate (2×50 mL) and thecombined ethyl acetate extracts were washed with H₂ O (2×20 mL) andbrine and dried (MgSO₄); the solvent was removed in vacuo. The productmixture was dissolved in methanol (20 mL), treated with anhydrous K₂ CO₃(500 mg), and vigorously stirred for 20 minutes. The reaction wasdiluted with ethyl acetate (75 mL) and washed with H₂ O (30 mL). Theaqueous phase was extracted with ethyl acetate (2×20 mL) and thecombined ethyl acetate extracts were washed with brine (2×20mL) anddried (MgSO₄). Purification by flash column chromatography (silica, 25%ethyl acetate in petroleum ether) gave a colorless solid: ¹ H NMR (250MHz, CDCl₃): δ 8.09 (d, J=15.8 Hz, 1H, olefin), 7.24 (d, J=8.6 Hz, 1H,5-pyridyl), 7.16 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.03 (d, J=15.8 Hz, 1H,olefin), 4.69 (d, J=4.2 Hz, 2H, CH₂), 4.03 (t, J=6.6 Hz, 2H, OCH₂), 3.82(s, 3H, CO₂ CH₃), 3.61 (t, J=4.2 Hz, 1H, OH), 1.91-0.85 (m, 23H,aliphatic); MS (CI): 378.3 (M+H).

5(f) 2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridinehydrochloride

2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(hydroxymethyl)pyridine (250mg, 0.662 mmol) was dissolved in dry toluene (10 mL) under an argonatmosphere and cooled to 0∞C. Thionyl chloride (0.50 mL, 6.85 mmol) wasslowly added and the solution was stirred at 0∞C for 30 minutes followedby 1 h at room temperature. The solvent and excess thionyl chloride wereremoved at reduced pressure. The crude hydrochloride salt was then useddirectly in the next step without further purification.

5(g) Methyl3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate

2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridinehydrochloride (0.662 mmol), prepared as previously described, wasdissolved in dry dimethylformamide (1 mL) and sequentially treated withmethyl 3-mercaptobenzoate (167 mg, 0.993 mmol), anhydrous Cs₂ CO₃ (970mg, 2.98 mmol), and tetrabutylammonium iodide (25 mg, 0.068 mmol) underan argon atmosphere. The reaction was heated at 65∞C for 45 minutes.Upon cooling to room temperature the reaction was diluted with ethylacetate (30 mL) and washed with H₂ O (2×15 mL) and brine and dried(MgSO₄). Purification by flash column chromatography (silica, petroleumether: CH₂ Cl₂ :ethyl acetate, 70:25:5) gave a colorless oil: ¹ H NMR(250 MHz, CDCl₃): δ 8.04 (s, 1H, 2-phenyl), 8.03 (d, J=15.7 Hz, 1H,olefin), 7.81 (d, J=7.9 Hz, 1H, 4-phenyl), 7.52 (d, J=7.9 Hz, 1H,6-phenyl), 7.31 (dd, J=7.9 Hz, 5-phenyl), 7.29 (d, J=8.6 Hz, 1H,5-pyridyl), 7.12 (d, J=8.6 Hz, 1H, 4-pyridyl), 6.98 (d, J=15.7 Hz, 1H,olefin), 4.26 (s, 2H, CH₂ S), 3.97 (t, J=6.6 Hz, 2H, OCH₂), 3.90 (s, 3H,CO₂ CH₃), 3.81 (s, 3H, CO₂ CH₃), 1.85-0.85 (m, 23H, aliphatic).

Proceeding in a similar manner, but substituting the appropriate thiolfor 3-mercaptobenzoate, and using known chemistry where appropriate, thefollowing compounds were made:

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]oxamicacid, dilithium salt,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]benzene,lithium salt,

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]anisole,lithium salt,

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]benzene-sulfonamide,dilithium salt

N-[3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]phenyl]-trifluoromethane-sulfonamide,dilithium salt, and

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoicacid, dilithium salt.

5(h) Methyl3-[1-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate

Methyl3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate(320 mg, 0.606 mmol) was dissolved in dry CH₂ Cl₂ (2.5 mL) and cooled to0∞C 85% m-Chloroperoxybenzoic acid (130 mg, 0.64 mmol) was added and thesolution was stirred for 10 minutes at 0∞C. The reaction was dilutedwith ethyl acetate (60 mL) and washed with saturated aqueous NaHCO₃(2×20 mL) and brine and dried (MgSO₄). Purification by flash columnchromatography (silica, CH₂ Cl₂ :petroleum ether:ethyl acetate,50:25:25) gave a colorless solid: ¹ H NMR (250 MHz, CDCl₃): δ 8.11 (d,J=7.9 Hz, 1H, 4-phenyl), 8.10 (s, 1H, 2-phenyl), 7.94 (d, J=15.7 Hz, 1H,olefin), 7.67 (d, J=7.9 Hz, 1H, 6-phenyl), 7.53 (dd, J=7.9 Hz, 1H,5-phenyl), 7.19 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.14 (d, J=8.6 Hz, 1H, 4-pyridyl), 6.68 (d, J=15.7 Hz, 1H, olefin), 4.21 (d, J=12.5 Hz, 1H, CHS),4.15 (d, J=12.5 Hz, 1H, CH'S), 3.99 (t, J=6.6 Hz, 2H, OCH₂), 3.93 (s,3H, CO₂ CH₃), 3.81 (s, 3H, CO₂ CH₃), 1.87-0.85 (m, 23H, aliphatic);Anal. Calcd. for C₃₀ H₄₁ O₆ NS: C, 66.27; H, 7.60; N, 2.58, found: C,65.97; H, 7.22; N, 2.46; MS (CI): 544.3 (M+H).

5(i)3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6pyridyl]ethyl]benzoicacid, dilithium salt

Methyl3-[1-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate(120 mg, 0.221 mmol) was dissolved in tetrahydrofuran (1.3 mL) andmethanol (0.66 mL) under an argon atmosphere and treated with 1M LiOH(0.66 mL, 0.66 mmol). The reaction was stirred at room temperature for18 hours. The tetrahydrofuran and methanol were removed under reducedpressure and the product was purified by Reversed Phased MPLC (RP-18silica, 10-65% methanol in H₂ O) and isolated by lyophilization to givea colorless amorphous solid: ¹ H NMR (250 MHz, CD₃ OD): δ 8.27 (s, 1H,2-phenyl), 8.11 (d, J=7.9 Hz, 1H, 4-phenyl), 7.77 (d, J=15.7 Hz, 1H,olefin), 7.60 (d, J=7.9 Hz, 1H, 6-phenyl), 7.58 (dd, J=7.9 Hz, 1H,5-phenyl), 7.27 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.04 (d, J=15.7 Hz, 1H,olefin), 7.01 (d, J=8.6 Hz, 1H, 4-pyridyl), 4.33 (d, J=12.5 Hz, 1H,CHS), 4.25 (d, J=12.5 Hz, 1H, CH'S), 4.04 (t, J=6.5 Hz, 2H, OCH₂),1.88-0.86 (m, 23H, aliphatic); Anal. Calcd. for C₂₈ H₃₅ O₆ NSLi₂.2H₂ O:C, 59.68; H, 6.97; N, 2.49, found: C, 59.49; H, 6.98; N, 2.58; FAB-MS:(+ve), 528.5 (M+H).

EXAMPLE 63-[1-Dioxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt 6(a) Methyl3-[1-dioxythia-2-[2-(E-2-carboxymethyl-ethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate

Methyl3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate(107 mg, 0.197 mmol) was dissolved in dry CH₂ Cl₂ (2 mL), cooled to 0∞C,and treated with 85% m-chloroperoxybenzoic acid (44 mg, 0.217 mmol). Thereaction was stirred at 0∞C for 1.5 hours. The reaction was diluted withethyl acetate (30 mL) and washed with saturated aqueous NaHCO₃ (15 mL)and brine and dried (MgSO₄). The product was purified by flash columnchromatogrphy (silica, petroleum ether: CH₂ Cl₂ :ethyl acetate,60:25:15) to give a colorless solid: ¹ H NMR (250 MHz, CDCl₃): δ 8.30(s, 1H, 2-phenyl), 8.26 (d, J=7.7 Hz, 1H, 4-phenyl), 7.83 (d, J=7.7 Hz,1H, 6-phenyl), 7.82 (d, J=15.7 Hz, 1H, olefin), 7.55 (dd, J=7.7 Hz, 1H,5-phenyl), 7.42 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.21 (d, J=8.6 Hz, 1H,4-pyridyl), 6.28 (d, J=15.7 Hz, 1H, olefin), 4.52 (s, 2H, CH₂ SO₂), 4.00(t, J=6.6 Hz, 2H, OCH₂), 3.92 (s, 3H, CO₂ CH₃), 3.78 (s, 3H, CO₂ CH₃),1.87-0.85 (m, 23H, aliphatic); Anal. Calcd. for C₃₀ H₄₁ O₇ NS: C, 64.38;H, 7.38; N, 2.50, found: C, 64.71; H, 7.41; N, 2.57; MS (CI): 560.3(M+H).

6(b)3-[1-Dioxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt

Methyl3-[1-dioxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate(20, 170 mg, 0.303 mmol) was dissolved in tetrahydrofuran (3.0 mL) andmethanol (1.0 mL) and treated with 1M LiOH (1.0 mL, 1.0 mmol). Thereaction was stirred at room temperature for 24 hours. Thetetrahydrofuran and methanol were removed under reduced pressure and theproduct was purified by Reversed Phased MPLC (RP-18 silica, 10-65%methanol in H₂ O) and isolated by lyophilization to give a colorlessamorphous solid: ¹ H NMR (250 MHz, CD₃ OD): δ 8.40 (s, 1H, 2-phenyl),8.22 (d, J=7.9 Hz, 1H, 4-phenyl), 7.69 (d, J=7.9 Hz, 1H, 6-phenyl), 7.67(d, J=15.7 Hz, 1H, olefin), 7.53 (dd, J=7.9 Hz, 1H, 5-phenyl), 7.30 (d,J=8.6 Hz, 1H, 5-pyridyl), 7.18 (d, J=8.6 Hz, 1H, 4-pyridyl), 6.85 (d,J=15.7 Hz, 1H, olefin), 4.62 (s, 2H, CH₂ SO₂), 4.03 (t, J=6.5 Hz, 2H,OCH₂), 1.87-0.86 (m, 23H, aliphatic); Anal. Calcd. for C₂₈ H₃₅ O₇NSLi₂.7/4H₂ O: C, 58.48; H, 6.74; N, 2.44, found: C, 58.58; H, 6.74; N,2.67; FAB-MS: (+ve), 544.3 (M+H); (-ve), 536.2 (M-Li).

EXAMPLE 74-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt

4-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt, was prepared according to the procedure describedfor3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt substituting methyl 4-mercaptobenzoate for methyl3-mercaptobenzoate.

7(a) Methyl4-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate

¹ H NMR (250 MHz, CDCl₃): δ 8.05 (d, J=15.7 Hz, 1H, olefin, 7.90 (d,J=8.5 Hz, 2H, aryl), 7.37 (d, J=8.5 Hz, 2H, aryl), 7.35 (d, J=8.6 Hz,1H, 5-pyridyl), 7.14 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.01 (d, J=15.7 Hz,1H, olefin), 4.29 (s, 2H, CH₂ S), 3.98 (t, J=6.5 Hz, 2H, OCH₂), 3.88 (s,3H, CO₂ CH₃), 3.86 (s, 3H, CO₂ CH₃), 1.86-0.85 (m, 23H, aliphatic).

7(b) Methyl4-[1-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate

mp. 107-109∞C; ¹ H NMR (250 MHz, CDCl₃) δ 8.13 (d, J=8.5 Hz, 2H, aryl),7.95 (d, J=15.7 Hz, 1H, olefin), 7.56 (d, J=8.5 Hz, 2H, aryl), 7.18 (d,J=8.6 Hz, 1H, 5-pyridyl), 7.11 (d, J=8.6 Hz, 1H, 4-pyridyl), 6.62 (d,J=15.7 Hz, 1H, olefin), 4.22 (d, J=12.5 Hz, 1H, CHS), 4.13 (d, J=12.5Hz, 1H, CH'S), 4.03 (t, J=6.5 Hz, 2H, OCH₂), 3.99 (s, 3H, CO₂ CH₃), 3.78(s, 3H, CO₂ CH₃), 1.92-0.85 (m, 23H, aliphatic); Anal. Calcd. for C₃₀H₄₁ O₆ NS: C, 66.27; H, 7.60; N, 2.58, found: C, 65.99; H, 7.55; N,2.27; MS (CI): 544 (M+H).

7(c)4-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt

mp. 205-207∞C (dec.); ¹ H NMR (250 MHz, CD₃ OD): δ 8.09 (d, J=8.5 Hz,2H, aryl), 7.78 (d, J=15.7 Hz, 1H, olefin), 7.59 (d, J=8.5 Hz, 2H,aryl), 7.26 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.07 (d, J=15.7 Hz, 1H,olefin), 6.98 (d, J=8.6 Hz, 1H, 4-pyridyl), 4.33 (d, J=12.5 Hz, 1H,CHS), 4.22 (d, J=12.5 Hz, 1H, CH'S), 4.04 (t, J=6.5 Hz, 2H, OCH₂),1.88-0.86 (m, 23H, aliphatic); Anal. Calcd. for C₂₈ H₃₅ O₆ NSLi₂.3/2H₂O: C, 60.64; H, 6.91; N, 2.53, found: C, 60.41; H, 6.73; N, 2.60;FAB-MS: (+ve), 528.5 (M+H).

EXAMPLE 82-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt

2-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt, was prepared according to the procedure describedfor3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt, but substituting methyl 2-mercaptobenzoate formethyl 3-mercaptobenzoate.

8(a) Methyl2-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate

¹ H NMR (250 MHz, CDCl₃): δ 8.07 (d, J=15.7 Hz, 1H, olefin), 7.96 (d,J=7.8 Hz, 1H, 3-phenyl), 7.56 (d, J=7.8 Hz, 1H, 6-phenyl), 7.43 (d,J=8.6 Hz, 1H, 5-pyridyl), 7.42 (m, 1H, aryl), 7.14 (d, J=8.6 Hz, 1H,4-pyridyl), 7.10 (m, 1H, aryl), 7.06 (d, J=15.7 Hz, 1H, olefin), 4.27(s, 2H, CH₂ S), 3.98 (t, J=6.6 Hz, 2H, OCH₂), 3.91 (s, 3H, CO₂ CH₃),3.83 (s, 3H, CO₂ CH₃), 1.86-0.86 (m, 23H, aliphatic).

8(b) Methyl2-[1-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate

mp. 60-62∞C; ¹ H NMR (250 MHz, CDCl₃): δ 8.13 (d, J=7.8 Hz, 1H,3-phenyl), 7.87 (d, J=15.7 Hz, 1H, olefin), 7.68 (d, J=7.8 Hz, 1H,6-phenyl), 7.53 (m, 2H, aryl), 7.33 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.16(d, J=8.6 Hz, 1H, 4-pyridyl), 6.46 (d, J=15.7 Hz, 1H, olefin), 4.42 (d,J=12.6 Hz, 1H, CHS), 4.30 (d, J=12.6 Hz, 1H, CH'S), 4.03 (s, 3H, CO₂CH₃), 4.0 (t, J=6.6 Hz, 2H, OCH₂), 3.81 (s, 3H, CO₂ CH₃), 1.87-0.85 (m,23H, aliphatic; Anal. Calcd. for C₃₀ H₄₁ O₆ NS: C, 66.27; H, 7.60; N,2.58, found: C, 66.37; H, 7.67; N, 2.56; MS (CI): 544 (M+H).

8(c) 2-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt

mp. 235∞C (dec); ¹ H NMR (250 MHz, CD₃ OD): δ 8.07 (d, J=7.8 Hz, 1H,3-phenyl), 7.76 (d, J=7.8 Hz, 1H, 6-phenyl), 7.71 (d, J=15.7 Hz, 1H,olefin), 7.53 (m, 2H, aryl), 7.31 (s, 2H, pyridyl), 6.92 (d, J=15.7 Hz,1H, olefin), 4.72 (d, J=12.6 Hz, 1H, CHS), 4.12 (d, J=12.6 Hz, 1H,CH'S), 4.05 (t, J=6.5 Hz, 2H, OCH₂), 1.88-0.86 (m, 23H, aliphatic);FAB-MS: (+ve), 523.3 (M+H).

In addition, by substituting the appropriate reagents and intermediatesfor those recited in 4(a)-4(c), and by using chemistry available in theart, the following compounds were made:

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoicacid, dilithium salt,

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]phenyl]trifluoro-methanesulfonamide,dilithium salt,

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]trifluoro-methanesulfonamide,dilithium salt,

N-[3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]-benzenesulfonamide,dilithium salt

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]anisole,lithium salt,

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzene,lithium salt.

EXAMPLE 93-[1-Oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt 9(a) Methyl3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyl-oxy-6-pyridyl]ethyl]benzoate

2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)pyridinehydrochloride, prepared as per Example 1(a)-1(f), was dissolved in drydimethylformamide (2 mL) and treated sequentially with methyl3-hydroxybenzoate (152 mg, 1.00 mmol, Aldrich), anhydrous K₂ CO₃ (500mg, 3.62 mmol), and tetrabutylammonium iodide (24.4 mg, 0.066 mmol)under an argon atmosphere. The reaction was heated at 90∞C for 1 hour.Upon cooling to room temperature the reaction was diluted with ethylacetate (50 mL) and washed with H₂ O (3×15 mL) and brine and dried(MgSO₄). Purification by flash column chromatography (silica, CH₂ Cl₂:petroleum ether:ethyl acetate, 50:48:2) gave a colorless solid: ¹ H NMR(250 MHz, CDCl₃): δ 8.09 (d, J=15.8 Hz, 1H, olefin), 7.69 (s, 1H,2-phenyl); 7.65 (d, J=7.9 Hz, 1H, 4-phenyl), 7.44 (d, J=8.6 Hz, 1H,5-pyridyl), 7.34 (dd, J=7.9 Hz, 1H, 5-phenyl), 7.22 (d, J=8.6 Hz, 1H,4-pyridyl), 7.16 (d, J=7.9 Hz, 1H, 6-phenyl), 7.07 (d, J=15.8 Hz, 1H,olefin), 5.18 (s, 2H, CH₂), 4.02 (t, J=6.6 Hz, 2H, OCH₂), 3.91 (s, 3H,CO₂ CH₃), 3.82 (s, 3H, CO₂ CH₃), 1.90-0.88 (m, 23H, aliphatic): Anal.Calcd. for C₃₀ H₄₁ O₆ N.1/8 mole toluene: C, 70.88; H, 8.09; N, 2.68,found: C, 70.98; H, 8.19; N, 2.64; MS (CI): 512.4 (M+H).

9(b)3-[1-Oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, dilithium salt

Methyl3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate(80 mg, 0.156 mmol) was dissolved in tetrahydrofuran (1.34 mL) andmethanol (0.50 mL) and treated with 1M LiOH (0.50 mL, 0.50 mmol). Thereaction was stirred at room temperature for 20 hours. Thetetrahydrofuran and methanol were removed at reduced pressure and theproduct was purified by Reversed Phased MPLC (RP-18 silica, 10-65%methanol in H₂ O) and isolated by lyophilization to give a colorlessamorphous solid: ¹ H NMR (250 MHz, CD₃ OD): δ-7.81 (d, J=15.7 Hz, 1H,olefin), 7.62 (s, 1H, 2-phenyl), 7.56 (d, J=7.9 Hz, 1H, 4phenyl), 7.44(d, J=8.6 Hz, 1H, 5-pyridyl), 7.40 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.26(dd, J=7.9 Hz, 1H, 5-phenyl), 7.07 (d, J=15.7 Hz, 1H, olefin), 7.05 (d,J=7.9 Hz, 1H, 6-phenyl), 5.13 (s, 2H, CH₂), 4.07 (t, J=6.5 Hz, 2H,OCH₂), 1.89-0.89 (m, 23H, aliphatic); Anal. Calcd, for C₂₈ H₃₅ O₆NLi₂.5/2H₂ O;: C, 62.22; H, 7.46; N, 2.59, found: C, 62.06; H, 7.37; N,2.82; FAB-MS: (+ve), 502.3 (M+Li); (-ve), 488.2 (M-Li).

9(c)3-[1-Oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, N-oxide, dilithium salt

Methyl3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3dodecyloxy-6-pyridyl]ethyl]benzoate,N-oxide. Methyl3-[1-oxa-2-[2-(E-2carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate(130 mg, 0.254 mmol) was dissolved in dry CH₂ Cl₂ (1.5 mL), cooled to0∞C, and treated with 85% m-chloroperoxybenzoic acid (57 mg, 0.28 mmol).The reaction was stirred at 0∞C for 10 minutes and then for 20 hours atroom temperature. The reaction was diluted with ethyl acetate (30 mL)and washed with saturated aqueous NaHCO₃ (15 mL), H₂ O (10 mL), andbrine and dried (MgSO₄). The product was purified by flash columnchromatography (silica, CH₂ Cl₂ :petroleum ether:ethyl acetate,50:40:10) to give a colorless solid: ¹ H NMR (250 MHz, CDCl₃): δ 8.24(d, J=16.2 Hz, 1H, olefin), 7.71 (d, J=8.0 Hz, 1H, 4-phenyl), 7.68 (s,1H, 2-phenyl), 7.60 (d, J=16.2 Hz, 1H, olefin), 7.46 (d, J=9.0 Hz, 1H,5-pyridyl), 7.38 (dd, J=8.0 Hz, 1H, 5-phenyl), 7.22 (d, J=8.0 Hz, 1H,6-phenyl), 6.9 (d, J=9.0 Hz, 1H, 4-pyridyl), 5.32 (s, 2H, CH₂), 4.10 (t,J=6.6 Hz, 2H, OCH₂), 3.92 (s, 3H, CO₂ CH₃), 3.83 (s, 3H, CO₂ CH₃),1.94-0.88 (m, 23H, aliphatic); Anal.Calcd. for C₃₀ H₄₁ O₇ N: C, 68.29;H, 7.83; N, 2.65, found: C, 68.27; H, 7.82; N, 2.66; MS (CI): 528.3(M+H).

9(d)3-[1-Oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, N-oxide, dilithium salt

Methyl3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoate,N-oxide (110 mg, 0.208 mmol) was dissolved in tetrahydrofuran (2 mL) andmethanol (0.65 mL) and treated with 1M LiOH (0.65 mL). The reaction wasstirred at room temperature for 20 hours. The tetrahydrofuran andmethanol were removed under reduced pressure and the product waspurified by Reversed Phase MPLC (RP-18 silica, 10-65% methanol in H₂ O)and isolated by lyophilization to give a colorless amorphous solid. ¹ HNMR (250 MHz, CD₃ OD): δ 7.99 (d, J=16.2 Hz, 1H, olefin), 7.64 (s, 1H,2-phenyl), 7.60 (d, J=8.0 Hz, 1H, 4-phenyl), 7.52 (d, J=9.0 Hz,

1H, 5-pyridyl), 7.45 (d, J=16.2 Hz, 1H, olefin), 7.30 (d, J=9.0 Hz, 1H,4-pyridyl), 7.29 (dd, J=8.0 Hz, 1H, 5-phenyl), 7.08 (d, J=8.0 Hz, 1H,6-phenyl), 5.30 (s, 2H, CH₂), 4.17 (t, J=6.6 Hz, 2H, OCH₂), 1.95-0.86(m, 23H, aliphatic); Anal. Calcd. for C₂₈ H₃₅ O₇ NLi₂.3H₂ O: C, 59.47;H, 7.31; N, 2.48, found: C, 59.46; H, 6.91; N, 2.50; FAB-MS: (+ve),512.2 (M+H); (-ve), 504.5 (M-Li)

Proceeding in a similar manner, but substituting the appropriateintermediates, the following compounds were made:

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6-pyridyl]ethyl]benzoicacid, N-oxide, dilithium salt,

3-[1-oxa-2-[2-(E,E-4-carboxybuta-1,3-dienyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoicacid, N-oxide, dilithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-nonyloxy)-6-pyridyl]ethyl]benzoicacid, N-oxide, dilithium salt,

N-[3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]phenyl]trifluoromethane-sulfonamide,N-oxide, dilithium salt,

4-methoxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzoicacid, dilithium salt,

N-[3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]acetamide,N-oxide, lithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(7-(4-methoxybenzyl-sulfonyl)heptyloxy)-6-pyridyl]ethyl]benzoicacid, N-oxide, dilithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(7-(4-methoxyphenyl-sulfonyl)heptyloxy)-6-pyridyl]ethyl]benzoicacid, N-oxide, dilithium salt,

3-[1-oxa-2-[2-(E-2-diethylphosphonoethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, N-oxide, lithium salt,

N-[3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]oxamicacid, dilithium salt,

N-[6-methoxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy-6-pyridyl]ethyl]phenyl]-trifluoromethane-sulfonamide,N-oxide, dilithium salt,

N-[6-methoxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]phenyl]-trifluoromethane-sulfonamidedilithium salt,

N-[3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]phenyl]oxamicacid, N-oxide, dilithium salt,

3-[1-oxa-2-[2-(E-2-ethylphosphonoethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid, N-oxide, dilithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]benzene,lithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]phenylurea,lithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]benzonitrile,lithium salt,

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]phenol,lithium salt, and

3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]benzamide,lithium salt.

EXAMPLE 103-[1-Oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]anilinelithium salt 10(a) 7-Octyn-1-ol

35% KH in mineral oil (27 g, 240 mmol) under an argon atmosphere waswashed with hexane and treated dropwise with 1,3-diaminopropane. Themixture was stirred at room temperature until it became homogeneous. Theflask was cooled to 0° C. and 3-octyn-1-ol (10 g, 79 mmol, LancasterSynthesis) was slowly added. The reaction was then stirred at roomtemperature for 18 hours. The reaction was quenched with H₂ O (50 mL)and the product was extracted into ether. The organic layer was washedwith 10% HCl and brine and dried (MgSO₄). Evaporation gave a colorlessoil which was used without further purification: ¹ H NMR (90 MHz, CDCl₃)δ 3.65 (t, J=5 Hz, 2H, O--CH₂), 2.23 (m, 2H, CH₂), 2.0 (m, 1H,acetylenic), 1.7-1.2 (m, 8H, (CH₂)₄); IR (neat) n_(max) 3350, 2930, 2125cm⁻¹.

10(b) 7-Octyn-1-^(t) butyldiphenylsilyl ether

To a cooled (0° C.) solution of 7-octyn-1-ol (9.3 g, 73.7 mmol) in DMF(70 mL) under an argon atmosphere was added imidazole (7.5 g, 110 mmol)followed by the dropwise addition of ^(t) butylchlorodiphenylsilane. Thereaction was then stirred at room temperature for 2 hours. The reactionsolution was diluted with Et₂ O and washed with H₂ O and brine and dried(MgSO₄). Purification by flash column chromatography (silica, 3% EtOAcin hexane) provided a colorless oil: ¹ H NMR (250 MHz, CDCl₃) δ 7.7 (d,4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, O--CH₂), 2.23 (m, 2H, CH₂),1.97 (t, 1H, acetylenic), 1.6-1.3 (m, 8H, (CH₂)₄), 10.5 (s, 9H, ^(t)butyl); IR (film) n_(max) 3321, 2940, 2125 cm⁻¹.

10(c) 8-(4-Methoxyphenyl)-7-octyn-1-^(t) butyldiphenylsilyl ether

To a flame dried flask containing triethylamine (140 mL) under an argonatmosphere was added 4-iodoanisole (13.3 g, 56.9 mmol),7-octyn-1-t-butyldiphenylsilyl ether (24.9 g, 68.3 mmol), (Ph₃ P)₂ PdCl₂catalyst (793 mg, 1.13 mmol) and CuI (431 mg, 2.27 mmol). The resultingmixture was heated at 50° C. for 4 hours. Upon cooling to roomtemperature the reaction mixture was filtered, the solids were washedwith Et₂ O and the solvent was evaporated. The residue was diluted withEt₂ O and washed with 5% HCl, H₂ O, NaHCO₃, and brine and dried (MgSO₄).Purification by flash column chromatography (silica, 2% EtOAc in hexane)gave an orange oil: ¹ H NMR (250 MHz, CDCl₃) δ 7.7 (d, 4H, aryl), 7.4(m, 6H, aryl), 7.35 (d, 2H, aryl); 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe),3.7 (t, 2H, O--CH₂), 2.4 (t, 2H, CH₂), 1.7-1.3 (m, 8H, (CH₂)₄), 1.05 (s,9H, ^(t) butyl).

10(d) 8-(4-Methoxyphenyl)octan-1-^(t) butyldiphenylsilyl ether

8-(4-Methoxyphenyl)-7-octyn-1-t-butyldiphenylsilyl ether (30 g, 63.7mmol) was dissolved in EtOH (125 mL) and EtOAc (125 mL) and treated with5% Pd--C catalyst (3 g). The reaction was vigorously stirred under an H₂atmosphere (balloon pressure) for 4 hours. The reaction mixture wasfiltered through a pad of celite and the solvent was evaporated. Theresulting pale yellow oil was pure by nmr analysis and was used directlyfor the next step: ¹ H NMR (250 MHz, CDCl₃) δ 7.7 (d, 4H, aryl), 7.4 (m,6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe), 3.6(t, 2H, O--CH₂), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH₂)₆), 1.0(s, 9H, ^(t) butyl).

10(e) 8-(4-Methoxyphenyl)octan-1-ol

To a cooled (0° C.) solution of 8-(4-methoxyphenyl)octan-1-^(t)butyldiphenylsilyl ether (63 mmol) was added tetrabutylammonium fluoride(70 mL, 70 mmol; 1M solution in THF). The cooling bath was removed andthe reaction was stirred at room temperature for 4.5 hours. The solventwas evaporated and the residue was dissolved in Et₂ O. This was washedwith H₂ O, 5% HCl, NaHCO₃, and brine and dried (MgSO₄). Purification byflash column chromatography (silica, 30% EtOAc in hexane) gave acolorless solid: ¹ H NMR (250 MHz, CDCl₃) δ 7.15 (d, 2H, aryl), 6.86 (d,2H, aryl), 3.85 (s, 3H, OMe), 3.68 (t, 2H, O--CH₂), 2.62 (t, 2H,benzylic), 1.75-1.3 (m, 12H, (CH₂)₆); MS (CI): 254.2 (M+NH₄); mp 47°-49°C.

10(f) 1-Iodo-8-(4-methoxyphenyl)octane

To a stirred solution of 8-(4-methoxyphenyl)octan-1-ol (12.3 g, 52 mmol)in dry toluene (200 mL) under an argon atmosphere was addedtriphenylphosphine (17.8 g, 67.6 mmol) and imidazole (10.6 g, 156 mmol).After the imidazole had dissolved I₂ (17.1 g, 67.6 mmol) was added. Thereaction was then heated at 65° C. for 30 minutes. Upon cooling to roomtemperature the reaction was concentrated to 1/4 volume. The remainingsolution was diluted with Et₂ O and washed with H₂ O and brine and dried(MgSO₄). The solvent was removed and the resulting residue was dissolvedin CH₂ Cl₂ and applied to a flash chromatography column (silica).Elution with 2% EtOAc in hexane provided a colorless oil (slightcontamination with triphenylphosphine): ¹ H NMR (250 MHz, CDCl₃) δ 7.08(d, J=8.6 Hz, 2H, aryl), 6.82 (d, J=8.6 Hz, 2H, aryl), 3.78 (s, 3H,OMe), 3.17 (t, J=7.4 Hz, 2H, I--CH₂), 2.54 (t, J=7.6 Hz, 2H, benzylic),1.85 (m, 2H, CH₂), 1.60 (m, 2H, CH₂), 1.31 (m, 8H, aliphatic); MS (CI):364.2 (M+NH₄).

10(g) 3-Hydroxy-6-methyl-2-pyridine carboxaldehyde

2.6-Lutidine-a²,3-diol (15 g, 107.8 mmol; Aldrich) was suspended in dryCH₂ Cl₂ (200 mL) and treated with MnO₂ (47 g, 539 mmol). The reactionwas stirred at room temperature for 6 hours. The reaction mixture wasfiltered through a pad of celite and the solvent was evaporated. Thecrude aldehyde was obtained as a tan solid and was used directly for thenext step: ¹ H NMR (250 MHz, CDCl₃) δ 10.65 (s, 1H, OH), 10.30 (s, 1H,aldehyde), 7.30 (m, 2H, 4,5-pyridyl), 2.55 (s, 3H, methyl).

10(f) 3-[8-(4-Methoxyphenyl)octyloxy]-6-methyl-2-pyridine carboxaldehyde

To a solution of 1-iodo-8(4-methoxyphenyl)octane (16.3 g, 47.1 mmol) indry DMF (45 mL) under an argon atmosphere was added3-hydroxy-6-methyl-2-pyridine carboxaldehyde (7.7 g, 56.2 mmol) andanhydrous K₂ CO₃ (32 g, 235 mmol). The reaction was vigorously stirredat 90° C. for 1.5 hours. Upon cooling to room temperature the reactionwas diluted with EtOAc and washed with H₂ O, aq NH₄ Cl, and brine anddried (MgSO₄). Evaporation provided crude aldehyde as a dark oil thatwas used without further purification.

10(g)2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine

3-[8-(4-Methoxyphenyl)octyloxy]-6-methyl-2-pyridine carboxaldehydeobtained above was dissolved in dry toluene (100 mL) under an argonatmosphere and treated with methyl (triphenylphosphoranylidene)acetate(16 g, 48 mmol). The reaction was heated for 1 hour at 50° C. Uponcooling to room temperature the reaction was diluted with EtOAc andwashed with H₂ O and brine and dried (MgSO₄). Purification by flashcolumn chromatography (silica, 20% EtOAc in hexane) gave a pale yellowoil: ¹ H NMR (250 MHz, CDCl₃) δ 8.07 (d, J=15.7 Hz, 1H, olefin), 7.10(m, 4H, phenyl, 4,5-pyridyl), 7.07 (d, J=15.7 Hz, 1H, olefin), 6.81 (d,J=8.6 Hz, 2H, phenyl), 3.97 (t, J=6.5 Ha, 2H, O--CH₂), 3.79 (s, 3H,methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6 Hz, 2H, benzylic), 2.48(s, 3H, methyl), 1.85 (m, 2H, CH₂), 1.60 (m, 2H, CH₂), 1.37 (m, 8H,aliphatic); MS (CI): 412.3 (M+H).

10(h)2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridineN-oxide

2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine(17.1 g, 41.5 mmol) was dissolved in dry CH₂ Cl₂ (105 mL) and cooled to0° C.; 50% mCPBA (15.8 g, 45.8 mmol) was added in three portions over 10minutes. The cooling bath was removed and the reaction was stirred for15 hours at room temperature. The reaction was poured into aqueousNaHCO₃ and the product extracted into CH₂ Cl₂. The organic extract waswashed with H₂ O and brine and dried (MgSO₄). The crude product wasobtained as a yellow solid and was used without further purification.

10(i)2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine

2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridineN-oxide obtained above was suspended in dry DMF (130 mL) and cooled to0° C. under an argon atmosphere. To this was slowly addedtrifluoroacetic anhydride (56 mL, 400 mmol). The reaction was maintainedat 0° C. for 20 minutes followed by 18 hours at room temperature. Thereaction solution was slowly added to a solution of saturated aqueousNa₂ CO₃ and stirred for 1 hour. The product was then extracted intoEtOAc; the combined organic extracts were washed with H₂ O and brine anddried (MgSO₄). Purification by flash chromatography (silica,EtOAc:hexane:CH₂ Cl₂, 30:20:50) gave a waxy solid: ¹ H NMR (250 MHz,CDCl₃) δ 8.08 (d, J=15.7 Hz, 1H, olefin), 7.23 (d, J=8.6 Hz, 1H,5-pyridyl), 7.16 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.09 (d, J=8.6 Hz, 2H,phenyl), 7.03 (d, J=15.7 Hz, 1H, olefin), 6.82 (d, J=8.6 Hz, 2H,phenyl), 4.69 (d, J=4.1 Hz, 2H, CH₂ --OH), 4.01 (t, J=6.5 Hz, 2H,O--CH₂), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.62 (t, J=4.1Hz, 1H, OH),2.55 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH₂), 1.58(m, 2H, CH₂), 1.44 (m, 8H, aliphatic; MS (CI): 428.2 (M+H).

10(j) 3-Aminophenol ^(t) butylcarbamate

3-Aminophenol (2.0 g, 18.3 mmol; Aldrich) was dissolved in CH₂ Cl₂ (18mL) and DMF (6 mL) and treated with di-^(t) butyl dicarbonate (5.0 mL,21.7 mmol). The reaction was stirred under an argon atmosphere for 18hours. The reaction solution was diluted with EtOAc and washed with H₂ Oand brine and dried (MgSO₄). Purification by flash column chromatography(silica, EtOAc:hexane:CH₂ Cl₂, 15:60:25) gave a colorless solid: ¹ H NMR(250 MHz, CDCl₃) δ 7.15 (m, 2H, aryl), 6.72 (m, 1H, aryl), 6.53 (m, 2H,aryl, OH), 6.0 (s, 1H, NH), 1.54 (s, 9H, ^(t) butyl); MS (CI): 210.2(M+H); mp 95°-97° C.

10(k)2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-[(3-amino)phenoxymethyl]pyridine^(t) butylcarbamate

To a cooled (0° C.) solution of SOCl₂ (0.51 mL, 7.0 mmol) in dry toluene(2 mL) under an argon atmosphere was added a solution of2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine(300 mg, 0.70 mmol) in toluene (5 mL). After 5 minutes the cooling bathwas removed and the reaction was stirred for 2 hours at roomtemperature. The toluene and excess SOCl₂ were evaporated. To this wasadded dry DMF (0.90 mL), 3-aminophenol ^(t) butylcarbamate (209 mg, 1.0mmol), and anhydrous Cs₂ CO₃ (1.63 g, 5.0 mmol). The reaction was heatedat 90° C. under an atmosphere of argon for 2 hours. Upon cooling to roomtemperature the reaction was diluted with EtOAc and washed with H₂ O,10% NaOH, H₂ O, and brine and dried (MgSO₄). Purification by flashcolumn chromatography (silica, EtOAc:hexane:CH₂ Cl₂, 7:63:30) yielded acolorless oil: ¹ H NMR (250 MHz, CDCl₃) δ 8.09 (d, J=15.7 Hz, 1H,olefin), 7.44 (d, J=8.6 Hz, 1H, aryl), 7.15 (m, 5H, aryl), 7.05 (d,J=15.7 Hz, 1H, olefin), 6.90 (m, 1H, aryl), 6.82 (d, J=8.6 Hz, 2H,aryl), 6.65 (m, 1H, aryl), 6.51 (s, 1H, NH), 5.12 (s, 2H, CH₂ --O), 4.0(t, J=6.5 Hz, 2H, O--CH₂), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H,OMe), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.88 (m, 2H, CH₂), 1.51 (s, 9H,^(t) butyl), 1.46 (m, 10H, aliphatic).

10(l)3-[1-Oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]aniline

2-(E-2-Carboxymethylethenyl)-3-[-(4-methoxyphenyl)-octyloxy]-6-[3-amino)phenoxymethyl]pyridine^(t) butylcarbamate (348 mg, 0.562 mmol) was dissolved in dry CH₂ Cl₂(3.0 mL) under an argon atmosphere and cooled to 0∞C. Anisole (0.09 mL,0.83 mmol) was added followed by trifluoroacetic acid (0.6 mL). Thereaction was stirred for 1 hour at 0° C. and then for 3 hours at roomtemperature. The reaction was quenched with aqueous NaHCO₃. The productwas extracted into CH₂ Cl₂ and the organic extracts were washed withbrine and dried (MgSO₄). Purification by flash column chromatography(silica, EtOAc:hexane:CH₂ Cl₂, 20:50:30) gave a pale yellow oil: ¹ H NMR(250 MHz, CDCl₃) δ 8.09 (d, J=15.7 Hz, 1H, olefin), 7.44 (d, J=8.6 Hz,1H, 5-pyridyl), 7.17 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.08 (m, 3H, aryl),7.05 (d, J=15.7 Hz, 1H, olefin), 6.88 (d, J=8.6 Hz, 2H, aryl), 6.42 (m,1H, aryl), 6.31 (m, 1H, aryl), 6.29 (m, 1H, aryl), 5.10 (s, 2H, CH₂--O), 4.02 (t, J=6.5 Hz, 2H, O--CH₂), 3.81 (s, 3H, methyl ester), 3.78(s, 3H, OMe), 3.70 (broad singlet, 2H, NH₂), 2.54 (t, J=7.6 Hz, 2H,benzylic), 1.88 (m, 2H, CH₂), 1.62 (m, 2H, CH₂), 1.40 (m, 8H,aliphatic); Analysis calcd for C₃₁ H₃₈ N₂ O₅.1/2H₂ O: C, 70.56; H, 7.45:N, 5.31; found C, 70.74; H, 7.36; N, 5.06; MS (CI): 519.3 (M+H).

10(m)3-[1-Oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6-pyridyl]ethyl]aniline,lithium salt

3-[1-Oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline(30 mg, 0.0578 mmol) was dissolved in THF (0.36 mL) and MeOH (0.24 mL)and treated with 1.0M LiOH (0.12 mL, 0.12 mmol). The reaction wasstirred under an argon atmosphere for 6 hours. The solvent wasevaporated and the product purified by Reversed Phased MPLC (RP-18silica, H₂ O--MeOH gradient). Lyophilization yielded a colorlessamorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.80 (d, J=15.7 Hz, 1H,olefin), 7.38 (s, 2H, 4,5-pyridyl), 7.06 (d, J=15.7 Hz, 1H, olefin),7.05 (d, J=8.6 Hz, 2H, phenyl), 6.97 (t, J=8.0 Hz, 1H, 5'-phenyl), 6.78(d, J=8.6 Hz, 2H, phenyl), 6.39 (m, 1H, 2'-phenyl), 6.35 (m, 2H,4',6'-phenyl), 5.04 (s, 2H, CH₂ --O), 4.04 (t, J=6.5 Hz, 2H, O--CH₂),3.74 (s, 3H, OMe), 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH₂),1.57 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic); Analysis calcd for C₃₀H₃₅ N₂ O₅ Li.9/4H₂ O: C, 65.38; H, 7.22; N, 5.08; found: C, 65.39; H,7.24; N, 5.23; MS (FAB): 511 (M+H), 517 (M+Li).

EXAMPLE 115-Carboxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,dilithium salt 11(a) 3-Amino-5-carboxymethylphenol

HCl gas was bubbled through a solution of 3-amino-5-hydroxybenzoic acidhydrochloride (1.9 g, 10 mmol; Lancaster Synthesis) in MeOH (50 mL) at0° C. for 30 minutes. The reaction was stopped and allowed to sit for 5hours. The solvent was removed in vacuo and the residue was dissolved inH₂ O. The aqueous solution was neutralized with 5% Na₂ CO₃ and theproduct was extracted into EtOAc. The organic solution was then dried(MgSO₄) and evaporated producing 1.5 g (89%) of ester as an off-whitesolid that was used without additional purification: ¹ H NMR (250 MHz,CDCl₃) δ 6.85 (dd, J=1.9 Hz, 1H, aryl), 6.80 (dd, J=1.9 Hz, 1H, aryl),6.30 (dd, J=1.9 Hz, 1H, aryl), 3.80 (s, 3H, methyl ester).

11(b) 3-Amino-5-carboxymethylphenol ^(t) butylcarbamate

A solution of 3-amino-5-carboxymethylphenol (1.5 g, 8.0 mmol) in DMF (8mL) under an argon atmosphere was treated with di-^(t) butyldicarbonate(2.1 g, 10 mmol). The reaction was stirred at room temperature for 16hours. The reaction was diluted with EtOAc and washed with H₂ O andbrine and dried (MgSO₄). Recrystallization from Et₂ O-hexane gave a tansolid: ¹ H NMR (250 MHz, CDCl₃) δ 7.35 (dd, J=1.9 Hz, 1H, aryl), 7.15(dd, J=1.9 Hz, 1H, aryl), 6.65 (dd, J=1.9 Hz, 1H, aryl), 6.45 (s, 1H,NH), 3.80 (s, 3H, methyl ester), 1.4 (s, 9H, ^(t) butyl).

11(c)2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-[(3-amino-5-carboxymethyl)phenoxymethyl]pyridine^(t) butylcarbamate

To a cooled (0° C.) solution of SOCl₂ (0.34 mL, 4.6 mmol) in dry toluene(1.5 mL) under an argon atmosphere was added a solution of2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine(197 mg, 0.46 mmol) in toluene (3 mL). After 5 minutes the cooling bathwas removed and the reaction was stirred for 2 hours at roomtemperature. The toluene and excess SOCl₂ were evaporated. To this wasadded dry DMF (1.0 mL), 3-amino-5-carboxymethylphenol ^(t)butylcarbamate (150 mg, 0.5 mmol), and anhydrous Cs₂ CO₃ (1.0 g, 3.0mmol). The reaction was heated at 90° C. under an atmosphere of argonfor 2 hours. Upon cooling to room temperature the reaction was dilutedwith EtOAc and washed with H₂ O, 10% NaOH, H₂ O, and brine and dried(MgSO₄). Purification by flash column chromatography (silica, 20% EtOAcin hexane) yielded a colorless oil: ¹ H NMR (250 MHz, CDCl₃) δ 8.09 (d,J=15.7 Hz, 1H, olefin), 7.55 (dd, J=1.9 Hz, 1H, aryl), 7.9 (dd, J=1.9Hz, 1H, aryl), 7.46 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.38 (dd, J=1.9 Hz,1H, aryl), 7.22 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.12 (d, J=8.6 Hz, 2H,phenyl), 7.07 (d, J=15.7 Hz, 1H, olefin), 6.82 (d, J=8.6 Hz, 2H,phenyl), 6.58 (s, 1H, NH), 5.16 (s, 2H, CH₂ --O), 4.04 (t, J=6.5 Hz, 2H,O--CH₂), 3.92 (s, 3H, methyl ester), 3.82 (s, 3H, methyl ester), 3.78(s, 3H, OMe), 2.58 (t, J=7.6 Hz, 2H, benzylic), 1.88 (m, 2H, CH₂), 1.55(s, 9H, ^(t) butyl), 1.46 (m, 10H, aliphatic); MS (CI): 677 M+H).

11(d)5-Carboxymethyl-3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline

2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-[(3-amino-5-carboxymethyl)phenoxymethyl]pyridine^(t) butylcarbamate (200 mg, 0.29 mmol) was dissolved in dry CH₂ Cl₂(3.0 mL) under an argon atmosphere and cooled to 0° C. Anisole (0.05 mL,0.46 mmol) was added followed by trifluoroacetic acid (0.3 mL). Thereaction was stirred for 30 minutes at 0° C. and then for 3.5 hours atroom temperature. The reaction was quenched with aqueous NaHCO₃. Theproduct was extracted into CH₂ Cl₂ and the organic extracts were washedwith brine and dried (MgSO₄). Purification by flash columnchromatography (silica, 25% EtOAc in hexane) gave a colorless oil: ¹ HNMR (250 MHz, CDCl₃) δ 8.09 (d, J=15.7 Hz, 1H, olefin), 7.44 (d, J=8.6Hz, 1H, 5-pyridyl), 7.17 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.08 (m, 3H,aryl), 7.05 (d, J=15.7 Hz, 1H, olefin), 6.96 (dd, J=1.9 Hz, 1H, aryl),6.88 (d, J=8.6 Hz, 2H, phenyl), 6.49 (dd, J=1.9 Hz, 1H, aryl), 5.12 (s,2H, CH₂ --O), 4.04 (t, J=6.5 Hz, 2H, O--CH₂), 3.92 (s, 3H, methylester), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH₂), 1.62 (m, 2H, CH₂), 1.40 (m, 8H,aliphatic); Analysis calcd for C₃₃ H₄₀ N₂ O₇.1/2H₂ O: C, 67.67; H, 7.06;N, 4.78; found: C, 67.42; H, 6.96; N, 4.69; MS (CI): 577 (M+H).

11(e)5-Carboxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,dilithium salt

5-Carboxymethyl-3-[1-oxa-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline(120 mg, 0.208 mmol) was dissolved in THF (1.0 mL) and MeOH (0.5 mL) andtreated with 1.0M LiOH (0.5 mL, 0.5 mmol). The reaction was stirredunder an argon atmosphere for 16 hours. The solvent was evaporated andthe product purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded a colorless amorphous solid: ¹ H NMR(250 MHz, d⁴ -MeOH) δ 7.80 (d, J=15.7 Hz, 1H, olefin), 7.42 (d, J=8.6Hz, 1H, 5-pyridyl), 7.38 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.06 (d, J=15.7Hz, 1H, olefin), 7.05 (d, J=8.6 Hz, 2H, phenyl), 6.98 (dd, J=1.9 Hz, 1H,aryl), 6.92 (dd, J=1.9 Hz, 1H, aryl), 6.80 (d, J=8.6 Hz, 2H, phenyl),6.47 (dd, J=1.9 Hz, 1H, aryl), 5.11 (s, 2H, CH₂ --O), 4.05 (t, J=6.5 Hz,2H, O--CH₂), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.85(m, 2H, CH₂), 1.57 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic); Analysiscalcd for C₃₁ H₃₄ N₂ O₅ Li₂.21/5H₂ O: C, 58.04; H, 6.70; N, 4.36; found:C, 57.87; H, 6.34; N, 4.22; MS (FAB): 561 (M+H).

EXAMPLE 123-[1-Thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt 12(a)3-[1-Thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]aniline

To a cooled (0° C.) solution of SOCl₂ (0.26 ml, 3.5 mmol) in dry toluene(1 mL) under an argon atmosphere was added a solution of2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine(150 mg, 0.35 mmol) in toluene (2.5 mL). After 5 minutes the coolingbath was removed and the reaction was stirred for 2 hours at roomtemperature. The toluene and excess SOCl₂ were evaporated. The crudeproduct was dissolved in dry DMF (1 mL) and added to a solution ofsodium-3-aminothiophenoxide, prepared from 3-aminothiophenol (0.09 mL,0.85 mmol; Aldrich) and NaH (34 mg, 0.084 mmol; 60% in mineral oil) inDMF (2 mL), under an argon atmosphere. The reaction was stirred at roomtemperature for 3 hours. The reaction was diluted with EtOAc and washedwith H₂ O and brine and dried (MgSO₄). Purification by flash columnchromatography (silica, 30% EtOAc in hexane) gave a colorless solid: ¹ HNMR (250 MHz, CDCl₃) δ 8.06 (d, J=15.7 Hz, 1H, olefin), 7.27 (d, J=8.6Hz, 1H, 5-pyridyl), 7.08 (m, 5H, 4-pyridyl, 5'-phenyl, olefin, phenyl),6.81 (d, J=8.6 Hz, 2H, phenyl), 6.74 (m, 2H, 2',4'-phenyl), 6.46 (ddd,J=8.0, 1.9 Hz, 1H, 6'-phenyl), 4.20 (s, 2H, CH₂ --S), 3.96 (t, J=6.5 Hz,2H, O--CH₂), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.65 (broadsinglet, 2H, NH₂), 2.55 (t, J=7.6 Hz, 2H, benzylic), 1.83 (m, 2H, CH₂),1.60 (m, 2H, CH₂), 1.45 (m, 2H, CH₂), 1.35 (m, 6H, aliphatic); Analysiscalcd for C₃₁ H₃₈ N₂ O₄ S.1/4H₂ O: C, 69.06; H, 7.20; N, 5.20; found: C,69.02; H, 7.16; N, 5.21; MS (CI): 535 (M+H); mp 57°-60° C.

12(b)3-[1-Thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt

3-[1-Thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy-6-pyridyl]ethyl]aniline(75 mg, 0.14 mmol) was dissolved in THF (0.56 mL) and MeOH (0.28 mL) andtreated with 1.0M LiOH (0.28 mL, 0.28 mmol). The reaction was stirredunder an argon atmosphere for 6 hours. The solvent was evaporated andthe product purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded a colorless amorphous solid: ¹ H NMR(250 MHz, d⁴ -MeOH) δ 7.76 (d, J=15.7 Hz, 1H, olefin), 7.25 (d, J=8.6Hz, 1H, 5-pyridyl), 7.24 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.09 (d, J=8.6Hz, 2H, phenyl), 7.04 (d, J=15.7 Hz, 1H, olefin), 6.97 (dd, J=8.0 Hz,1H, 5'-phenyl), 6.80 (d, J=8.6 Hz, 2H, phenyl), 6.72 (dd, J=1.9 Hz, 1H,2'-phenyl), 6.67 (ddd, J=8.0, 1.9 Hz, 1H, 4'-phenyl), 6.51 (ddd, J=8.0,1.9 Hz, 1H, 6'-phenyl), 4.16 (s, 2H, CH₂ --S), 4.00 (t, J=6.5 Hz, 2H,O--CH₂), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.80 (m,2H, CH₂), 1.49 (m, 4H, aliphatic), 1.33 (m, 6H, aliphatic); Analysiscalcd for C₃₀ H₃₅ N₂ O₄ SLi.5/2H₂ O; C, 63.03; H, 7.05; N, 4.90; found:C, 62.67; H, 6.72; N, 4.72; MS (FAB): 527 (M+H), 521 (M+H; free acid).

Proceeding in a similar manner, but substituting the appropriateintermediates for those indicated here, and using chemistry well knownin the art, the following compounds were prepared:

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]ethyl]aniline,lithium salt;

Colorless amorphous solid: ¹ H NMR (360 MHz, d⁶ -DMSO) δ 7.43 (d, J=15.7Hz, 1H, olefin), 7.33 (d, J=8.6 Hz, 1H, pyridyl), 7.23 (d, J=8.6 Hz, 1H,pyridyl), 7.13 (d, J=8.6 Hz, 2H, phenyl), 6.92 (dd, J=7.8 Hz, 1H,5'-phenyl), 6.86 (d, J=15.7 Hz, 1H, olefin), 6.82 (d, J=8.6 Hz, 2H,phenyl), 6.61 (s, 1H, 2'-phenyl), 6.51 (d, J=7.8 Hz, 1H, 4'-phenyl),6.37 (d, J=7.8 Hz, 1H 6'-phenyl), 5.10 (broad singlet, 2H, NH₂), 4.16(s, 2H, CH₂ --S), 4.01 (t, J=6.5 Hz, 2H, O--CH₂), 3.72 (s, 3H, OMe),2.58 (t, J=7.6 Hz, 2H, benzylic), 1.71 (m, 4H, aliphatic); Analysiscalcd for C₂₆ H₂₇ N₂ O₄ SLi.13/4H₂ O: C, 62.20 ; H, 6.12; N, 5.58;found: C, 62.23; H, 5.82; N, 5.44; MS (ES⁺): 464.3 (M+; free acid);(ES⁻): 463.0 (M--H; free acid);

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt;

Colorless amorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.78 (d, J=15.7Hz, 1H, olefin), 7.53 (d, J=8.6 Hz, 2H, phenyl), 7.34 (d, J=8.6 Hz, 2H,phenyl), 7.25 (d, J=8.6 Hz, 1H, pyridyl), 7.24 (d, J=8.6 Hz, 1H,pyridyl), 7.04 (d, J=15.7 Hz, 1H, olefin), 6.97 (dd, J=8.0 Hz, 1H,5'-phenyl), 6.72 (dd, J=1.9 Hz, 1H, 2'-phenyl), 6.67 (ddd, J=8.0, 1.9Hz, 1H, 4'-phenyl), 6.51 (ddd, J=8.0, 1.9 Hz, 1H, 6'-phenyl), 4.16 (s,2H, CH₂ --S), 4.01 (t, J=6.5 Hz, 2H, O--CH₂), 2.68 (t, J=7.6 Hz, 2H,benzylic), 1.85 (m, 2H, CH₂), 1.68 (m, 2H, CH₂), 1.50 (m, 2H, CH₂), 1.37(m, 6H, aliphatic); Analysis calcd for C₃₀ H₃₂ F₃ N₂ O₃ SLi.11/2H₂ O: C,60.91; H, 5.96; N, 4.74; found: C, 60.53; H, 5.56; N, 4.51; MS (ES+):559.0 (M+H; free acid), (ES-): 557.0 (M-H; free acid); and

3-[1-thia-2-[2-(E-2-carboxyethenyl)-3)-(8phenyl)octyloxy-6-pyridyl]ethyl]aniline,lithium salt

Colorless amorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.72 (d, J=15.7Hz, 1H, olefin), 7.20 (m, 7H, pyridyl, phenyl), 7.04 (d, J=15.7 Hz, 1H,olefin), 6.97 (dd, J=8.0 Hz, 1H, 5'-phenyl), 6.72 (dd, J=1.9 Hz, 1H,2'-phenyl), 6.67 (ddd, J=8.0, 1.9 Hz, 1H, 4'-phenyl), 6.51 (ddd, J=8.0,1.9 Hz, 1H, 6'-phenyl), 4.16 (s, 2H, CH₂ --S), 4.02 (t, J=6.5 Hz, 2H,O--CH₂) 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.83 (m, 2H, CH₂), 1.59 (m,2H, CH₂), 1.50 (m, 2H, CH₂), 1.37 (m, 6H, aliphatic); MS (ES+): 491.0(M+H; free acid), (ES-): 489.0 (M-H; free acid).

EXAMPLE 133-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt 13(a)3-[1-Oxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline

To a cooled (-15° C.) solution of3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline(150 mg, 0.28 mmol) in CH₂ Cl₂ (4 mL) under an argon atmosphere wasadded 85% mCPBA (63 mg, 0.31 mmol) in two portions over 15 minutes. Thereaction was maintained at -15° C. for a total of 40 minutes. Thereaction was quenched with aq NaHCO₃ solution and the product extractedin EtOAc. The organic extract was washed with H₂ O and brine and dried(MgSO₄). The product was recrystallized from EtOAc-hexane to give acolorless solid: ¹ H NMR (250 MHz, CDCl₃) δ 8.03 (d, J=15.7 Hz, 1H,olefin), 7.22 (dd, J=8.0 Hz, 1H, 5'-phenyl), 7.15 (m, 2H, 4,5-pyridyl),7.11 (d, J=8.6 Hz, 2H, phenyl), 6.92 (m, 1H, 2'-phenyl), 6.85 (d, J=15.7Hz, 1H, olefin), 6.80 (m, 3H, phenyl, 4'-phenyl), 6.73 (ddd, J=8.0, 1.9Hz, 1H, 6'-phenyl), 4.12 (s, 2H, CH₂ --S), 4.00 (t, J=6.5 Hz, 2H,O--CH₂); 3.99 (broad singlet, 2H, NH₂), 3.82 (s, 3H, methyl ester), 3.79(s, 3H, OMe), 2.56 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH₂), 1.60(m, 2H, CH₂), 1.48 (m, 2H, CH₂), 1.36 (m, 6H, aliphatic); Analysis calcdfor C₃₁ H₃₈ N₂ O₅ S: C, 67.61; H, 6.95; N, 5.09; found: C, 67.73; H,7.17; N, 4.82; MS (CI): 551 (M+H); mp 109°-111° C.

13(b)3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxy-phenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt

3-[1-Oxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline(109 mg, 0.198 mmol) was dissolved in THF (0.80 mL) and MeOH (0.40 mL)and treated with 1.0M LiOH (0.40 mL, 0.40 mmol). The reaction wasstirred under an argon atmosphere for 6 hours. The solvent wasevaporated and the product purified by Reversed Phased MPLC (RP-18silica, H₂ O--MeOH gradient). Lyophilization yielded a colorlessamorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.75 (d, J=15.7 Hz, 1H,olefin), 7.28 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.15 (dd, J=8.0 Hz, 1H,5'-phenyl), 7.03 (m, 4H, 4-pyridyl, olefin, phenyl), 6.86 (dd, J=1.9 Hz,1H, 2'-phenyl), 6.75 (m, 4H, 4',6'-phenyl, phenyl), 4.20 (q, J=13 Hz,2H, CH₂ --S), 4.02 (t, J=6.5 Hz, 2H, O--CH₂), 3.72 (s, 3H, OMe), 2.52(t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH₂), 1.53 (m, 4H, aliphatic),1.37 (m, 6H, aliphatic); Analysis calcd for C₃₀ H₃₅ N₂ O₅ SLi.2H₂ O: C,62.27; H, 6.79; N, 4.84; found: C, 62.13; H, 6.89; N, 5.01; MS (FAB):543 (M+H), 537 (M+H; free acid).

Proceeding in a similar manner, there was made

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl))-6-pyridyl]ethyl]aniline,lithium salt;

Colorless amorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.75 (d, J=15.7Hz, 1H, olefin), 7.28 (d, J=8.6 Hz, 1H, pyridyl), 7.20 (d, J=8.6 Hz, 1H,pyridyl), 7.12 (d, J=8.6 Hz, 2H, phenyl), 7.06 (s, 1H, 2'-phenyl), 7.02(d, J=7.8 Hz, 1H, 4'-phenyl), 6.81 (m, 5H, 5',6'-phenyl, olefin,phenyl), 4.20 (q, J=13 Hz, 2H, CH₂ --S(O)), 4.02 (t, J=6.5 Hz, 2H,O--CH₂), 3.72 (s, 3H, OMe), 2.62 (t, J=7.6 Hz, 2H, benzylic), 1.80 (m,4H, aliphatic); Analysis calcd for C₂₆ H₂₇ N₂ O₅ SLi.25/8H₂ O: C, 58.50;H, 6.09; N, 5.25; found: C, 58.18; H, 5.67; N, 5.12; MS (ES⁺): 481.2(M+H; free acid), (ES-): 479.0 (M-H; free acid).

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-trifluoromethylphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt;

Colorless amorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.75 (d, J=15.7Hz, 1H, olefin), 7.53 (d, J=8.6 Hz, 2H, phenyl), 7.34 (d, J=8.6 Hz, 2H,phenyl), 7.24 (d, J=8.6 Hz, 1H, pyridyl), 7.18 (d, J=8.6 Hz, 1H,pyridyl), 7.04 (d, J=8.0 Hz, 1H, 4'-phenyl), 7.02 (d, J=15.7 Hz, 1H,olefin), 6.89 (s, 1H, 2'-phenyl), 6.78 (m, 2H, 5',6'-phenyl), 4.20 (q,J=13 Hz, 2H, CH₂ --S(O)), 4.02 (t, J=6.5 Hz, 2H, O--CH₂), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.88 (m, 2H, CH₂), 1.69 (m, 2H, CH₂), 1.50 (m, 2H,CH₂), 1.39 (m, 6H, aliphatic); Analysis calcd for C₃₀ H₃₂ F₃ N₂ O₄SLi.13/4H₂ O: C, 58.87; H, 5.85; N, 4.58; found: C, 58.92; H, 5.55; N,4.48; MS (ES+): 575.2 (M+H; free acid);

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-phenyl)octyloxy-6-pyridyl]ethyl]aniline,lithium salt;

Colorless amorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.75 (d, J=15.7Hz, 1H, olefin), 7.20 (m, 7H, pyridyl, phenyl), 7.04 (d, J=8.0 Hz, 1H,4'-phenyl), 7.02 (d, J=15.7 Hz, 1H, olefin), 6.89 (s, 1H, 2'-phenyl),6.78 (m, 2H, 5',6'-phenyl), 4.20 (q, J=13 Hz, 2H, CH₂ --S(O)), 4.02 (t,J=6.5 Hz, 2H, O--CH₂), 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.88 (m, 2H,CH₂), 1.69 (m, 2H, CH₂), 1.50 (m, 2H, CH₂), 1.39 (m, 6H, aliphatic);Analysis calcd for C₂₉ H₃₃ N₂ O₄ SLi.1H₂ O: C, 65.65; H, 6.65; N, 5.28;found: C, 65.62; H, 6.39; N, 4.90; MS (ES+): 507.0 (M+H; free acid),(ES-): 505.0 (M-H; free acid);

3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-fluorophenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt;

Colorless amorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.75 (d, J=15.7Hz, 1H, olefin), 7.30-6.90 (multiplet, 8H, pyridyl, phenyl, olefin,4'-phenyl), 6.89 (s, 1H, 2'-phenyl), 6.78 (m, 2H, 5',6'-phenyl), 4.20(q, J=13 Hz, 2H, CH₂ --S(O)), 4.02 (t, J=6.5 Hz, 2H, O--CH₂), 2.52 (t,J=7.6 Hz, 2H, benzylic), 1.88 (m, 2H, CH₂), 1.59 (m, 2H, CH₂), 1.50 (m,2H, CH₂), 1.39 (m, 6H, aliphatic); MS (ES+): 525.2 (M+H; free acid),(ES-): 523.0 (M-H; free acid.

EXAMPLE 143-[1-Dioxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt 14(a)3-[1-Dioxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline

To a cooled (0° C.) solution of3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline(75 mg, 0.14 mmol) in CH₂ Cl₂ (3 mL) under an argon atmosphere was added85% mCPBA (63 mg, 0.308 mmol). After 1 hour the reaction was quenchedwith aq NaHCO₃ solution and the product extracted into EtOAc. Theorganic extracts were washed with H₂ O and brine and dried (MgSO₄).Purification by flash column chromatography (silica, 50% EtOAc inhexane) gave a colorless solid: ¹ H NMR (250 MHz, CDCl₃) δ 7.90 (d,J=15.7 Hz, 1H, olefin), 7.39 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.21 (t,J=8.0 Hz, 1H, 5'-phenyl), 7.19 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.11 (d,J=8.6 Hz, 2H, phenyl), 7.03 (m, 2H, 2',4'-phenyl), 6.86 (m, 1H,6'-phenyl), 6.81 (d, J=8.6 Hz, 2H, phenyl), 6.54 (d, J=15.7 Hz, 1H,olefin), 4.46 (s, 2H, CH₂ --S), 3.99 (t, J=6.5 Hz, 2H, O--CH₂), 3.86(broad singlet, 2H, NH₂), 3.79 (s, 3H, methyl ester), 3.78 (s, 3H, OMe),2.55 (t, J=7.6 Hz, 2H, benzylic), 1.82 (m, 2H CH₂), 1.60 (m, 2H, CH₂),1.45 (m, 2H, CH₂), 1.35 (m, 6H, aliphatic); Analysis calcd for C₃₁ H₃₈N₂ O₆ S.1/3 mol C₆ H₁₄ : C, 66.57; H, 7.22; N, 4.70; found: C, 66.45; H,7.24; N, 4.89; MS (CI): 567 (M+H); mp 92°-95° C.

14(b)3-[1-Dioxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt

3-[1-Dioxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline(51 mg, 0.09 mmol) was dissolved in THF (0.30 mL) and MeOH (0.18 mL) andtreated with 1.0M LiOH (0.18 mL, 0.18 mmol). The reaction was stirredunder an argon atmosphere for 6 hours. The solvent was evaporated andthe product purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded a colorless amorphous solid: ¹ H NMR(250 MHz, d⁴ -MeOH) δ 7.65 (d, J=15.7 Hz, 1H, olefin), 7.26 (d, J=8.6Hz, 1H, 5-pyridyl), 7.24 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.17 (dd, J=8.0Hz, 1H, 5'-phenyl), 7.06 (d, J=8.6 Hz, 2H, phenyl), 6.97 (dd, J=1.9 Hz,1H, 2'-phenyl), 6.85 (m, 2H, 4',6'-phenyl), 6.78 (d, J=8.6 Hz, 2H,phenyl), 6.75 (d, J=15.7 Hz, 1H, olefin), 4.55 (s, 2H, CH₂ --S), 4.04(t, J=6.5 Hz, 2H, O--CH₂), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6 Hz, 2H,benzylic), 1.86 (m, 2H, CH₂), 1.55 (m, 4H, aliphatic), 1.37 (m, 6H,aliphatic); MS (FAB): 559 (M+H), 553 (M+H; free acid).

EXAMPLE 153-[1-Thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6pyridyl]ethyl]-N,N-dimethylaniline,lithium salt 15(a)3-[1-Thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline

To a solution of3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline(75 mg, 0.14 mmol) in acetonitrile (1 mL) was added formaldehyde (0.25mL, 3.1 mmol; 37% aqueous solution) and NaCNBH₃ (50 mg, 0.80 mmol). Thereaction was stirred at room temperature for 15 minutes. The reactionsolution was made neutral by the addition of glacial acetic acid andstirred for an additional 2 hours. The reaction was diluted with H₂ Oand the product extracted into EtOAc. The organic layer was washed withH₂ O and brine and dried (MgSO₄). Purification by flash columnchromatography (silica, 20% EtOAc in hexane) gave a pale yellow oil: ¹ HNMR (250 MHz, CDCl₃) δ 8.06 (d, J=15.7 Hz, 1H, olefin), 7.35 (d, J=8.6Hz, 1H, 5-pyridyl), 7.08 (m, 4H, 4-pyridyl, 5'-phenyl, phenyl), 7.04 (d,J=15.7 Hz, 1H, olefin), 6.83 (d, J=8.6 Hz, 2H, phenyl), 6.74 (m, 2H,2',4'-phenyl), 6.52 (dd, J=8.0, 1.9 Hz, 1H, 6'-phenyl), 4.23 (s, 2H, CH₂--S), 4.00 (t, J=6.5 Hz, 2H, O--CH₂), 3.82 (s, 3H, methyl ester), 3.78(s, 3H, OMe), 2.89 (s, 6H, Me₂), 2.55 (t, J=7.6 Hz, 2H, benzylic), 1.83(m, 2H, CH₂), 1.60 (m, 2H, CH₂), 1.45 (m, 2H, CH₂), 1.35 (m, 6H,aliphatic); MS (CI): 563 (M+H).

15(b)3-[1-Thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline,lithium salt

3-[1-Thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline(100 mg, 0.178 mmol) was dissolved in THF (0.72 mL) and MeOH (0.36 mL)and treated with 1.0M LiOH (0.36 mL, 0.36 mmol). The reaction wasstirred under an argon atmosphere for 6 hours. The solvent wasevaporated and the product purified by Reversed Phased MPLC (RP-18silica, H₂ O--MeOH gradient). Lyophilization yielded a colorlessamorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.78 (d, J=15.7 Hz, 1H,olefin), 7.25 (s, 2H, 4,5-pyridyl), 7.07 (m, 4H, phenyl, olefin,5'-phenyl), 6.80 (d, J=8.6 Hz, 2H, phenyl), 6.72 (dd, J=1.9 Hz, 1H,2'-phenyl), 6.67 (ddd, J=8.0, 1.9 Hz, 1H, 4'-phenyl), 6.55 (ddd, J=8.0,1.9 Hz, 1H, 6'-phenyl), 4.20 (s, 2H, CH₂ --S), 4.00 (t, J=6.5 Hz, 2H,O--CH₂), 3.76 (s, 3H, OMe), 2.85 (s, 6H, Me₂), 2.52 (t, J=7.6 Hz, 2H,benzylic), 1.85 (m, 2H, CH₂), 1.55 (m, 4H, aliphatic), 1.33 (m, 6H,aliphatic); Analysis calcd for C₃₂ H₃₉ N₂ O₄ SLi.5/4H₂ O: C, 66.59; H,7.25; N, 4.85; found: C, 66.50; H, 7.01; N, 4.75; MS (FAB): 555.2 (M+H).

EXAMPLE 163-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline,lithium salt 16(a)3-[1-Oxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylaniline

Prepared from3-[1-thia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylanilineaccording to the procedure described for the preparation of3-[1-oxythia-2-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline:¹ H NMR (250 MHz, CDCl₃) δ 8.01 (d, J=15.7 Hz, 1H, olefin), 7.22 (dd,J=8.0 Hz, 1H, 5'-phenyl), 7.17 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.13 (d,J=8.6 Hz, 1H, 4-pyridyl), 6.80 (m, 6H, phenyl, 2',4',6'-phenyl, olefin),4.12 (s, 2H, CH₂ --S), 4.00 (t, J=6.5 Hz, 2H, O--CH₂), 3.82 (s, 3H,methyl ester), 3.79 (s, 3H, OMe), 2.95 (s, 6H, Me₂), 2.55 (t, J=7.6 Hz,2H, benzylic), 1.85 (m, 2H, CH₂), 1.60 (m, 2H, CH₂), 1.48 (m, 2H, CH₂),1.36 (m, 6H, aliphatic); MS (CI): 579.2 (M+H).

16(b)3-[1-Oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N,-dimethylaniline,lithium salt

Prepared from3-[1-oxythia-2-[2-(E-2-carboxymethyl-ethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]-N,N-dimethylanilineaccording to the procedure described for the preparation of3-[1-oxythia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt. Colorless amorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ7.75 (d, J=15.7 Hz, 1H, olefin), 7.31 (dd, J=8.0 Hz, 1H, 5'-phenyl),7.24 (d, J=8.6 Hz, 1H, 5-pyridyl), 7.03 (m, 3H, 4-pyridyl, phenyl), 6.95(d, J=15.7 Hz, 1H, olefin), 6.80 (m, 4H, aryl), 6.70 (m, 1H, aryl), 4.21(q, J=13 Hz, 2H, CH₂ --S), 4.02 (t, J=6.5 Hz, 2H, O--CH₂), 3.74 (s, 3H,OMe), 2.84 (s, 6H, Me₂), 2.56 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H,CH₂), 1.53 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); MS (FAB): 571.3(M+H).

EXAMPLE 17 Preparation of3-[N-[2-[2-(E-2-Carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]methyl]]aminobenzoicacid, dilithium salt

The captioned compound was prepared according to the method set out inScheme 5 above by reacting the appropriate t-BOC-protected aminobenzoicacid with2-(E-2-carboxymethylethenyl)-3-dodecyloxy-6-(chloromethyl)-pyridinehydrochloride or a similar intermediate, the captioned compound wasprepared.

In a similar manner3-[N-[2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pridyl)-methyl]]aminobenzoicacid, N-oxide, dilithium salt and3-[N-[2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-octyloxy-6-pyridyl]methyl]-N-methyl]aminobenzoicacid, dilithium salt were made.

EXAMPLE 184-[2-Thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt 18(a). 3-Hydroxy-6-methyl-2-pyridine carboxaldehyde

2,6-Lutidine-a²,3-diol (15 g, 107.8 mmol; Aldrich) was suspended in dryCH₂ Cl₂ (200 mL) and treated with MnO₂ (47 g, 539 mmol). The reactionwas stirred at room temperature for 6 hours. The reaction mixture wasfiltered through a pad of Celite and the solvent was evaporated. Thecrude aldehyde was obtained as a tan solid and was used directly for thenext step: ¹ H NMR (250 MHz, CDCl₃) δ 10.65 (s, 1H, OH), 10.30 (s, 1H,aldehyde), 7.30 (m, 2H, 4,5-pyridyl), 2.55 (s, 3H, methyl).

18(b). 3-[8-(4-Methoxyphenyl)octyloxy]-6-methyl-2-pyridinecarboxaldehyde

To a solution of 1-iodo-8-(4-methoxyphenyl)octane (16.3 g, 47.1 mmol) indry DMF (45 mL) under an argon atmosphere was added3-hydroxy-6-methyl-2-pyridine carboxaldehyde (7.7 g. 56.2 mmol) andanhydrous K₂ CO₃ (32 g, 235 mmol). The reaction was vigorously stirredat 90° C. for 1.5 hours. Upon cooling to room temperature the reactionwas diluted with EtOAc and washed with H₂ O, aq NH₄ Cl, and brine anddried (MgSO₄). Evaporation provided crude aldehyde as a dark oil thatwas used without further purification.

18(c).2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-methylpyridine

3-[8-(4-methoxyphenyl)octyloxy]-6-methyl-2-pyridine carboxaldehydeobtained above was dissolved in dry toluene (100 mL) under an argonatmosphere and treated with methyl (triphenylphosphoranylidene)acetate(16 g, 48 mmol). The reaction was heated for 1 hour at 50° C. Uponcooling to room temperature the reaction was diluted with EtOAc andwashed with H₂ O and brine and dried (MgSO₄). Purification by flashcolumn chromatography (silica, 20% EtOAc in hexane) gave the product asa pale yellow oil: ¹ H NMR (250 MHz, CDCl₃) δ 8.07 (d, J=15.7 Hz, 1H,olefin), 7.10 (m, 4H, phenyl, 4,5-(pyridyl), 7.07 (d, J=15.7 Hz, 1H,olefin), 6.81 (d, J=8.6 Hz, 2H, phenyl), 3.97 (t, J=6.5 Hz, 2H, O--CH₂),3.79 (s, 3H, OCH₃), 3.78 (s, 3H, methyl ester), 2.54 (t, J=7.6 Hz, 2H,benzylic), 2.48 (s, 3H, methyl), 1.85 (m, 2H, CH₂), 1.60 (m, 2H, CH₂),1.37 (m, 8H, aliphatic); MS (CI): 412.3 (M+H).

18(d).2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-methylpyridineN-oxide

2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridine(17.1 g, 41.5 mmol) was dissolved in dry CH₂ Cl₂ (105 mL) and cooled to0° C.; 50% m-chlorperbenzoic acid (15.8 g, 45.8 mmol) was added in threeportions over 10 minutes. The cooling bath was removed and the reactionwas stirred for 15 hours at room temperature. The reaction was pouredinto aqueous NaHCO₃ and the product extracted into CH₂ Cl₂. The organicextract was washed with H₂ O and brine and dried (MgSO₄). The crudeproduct was obtained as a yellow solid and was used without furtherpurification.

18(e).2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-hydroxymethylpyridine

2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-methylpyridineN-oxide obtained above was suspended in dry DMF (130 mL) and cooled to0° C. under an argon atmosphere. To this was slowly addedtrifluoroacetic anhydride (56 mL, 400 mmol). The reaction was maintainedat 0° C. for 20 minutes followed by 18 hours at room temperature thereaction solution was slowly added to a solution of saturated aqueousNa₂ CO₃ and stirred for 1 hour. The product was then extracted intoEtOAc; the combined organic extracts were washed with H₂ O and brine anddried (MgSO₄). Purification by flash column chromatography (silica,EtOAc:hexane:CH₂ Cl₂, 30:20:50) gave a waxy solid: ¹ H NMR (250 MHz,CDCl₃) δ 8.08 (d, J=15.7 Hz, 1H, olefin), 7.23 (d, J=8.6 Hz, 1H,5-pyridyl), 7.16 (d, J=8.6 Hz, 1H, 4-pyridyl), 7.09 (d, J=8.6 Hz, 2H,phenyl), 7.03 (d, J=15.7 Hz, 1H, olefin), 6.82 (d, J=8.6 Hz, 2H,phenyl), 4.69 (d, J=4.1 Hz, 2H, CH₂ --OH), 4.01 (t, J=6.5 Hz, 2H,O--CH₂), 3.82 (s, 3H, OCH₃), 3.78 (s, 3H, methyl ester), 3.62 (t, J=4.1Hz, 1H, OH), 2.55 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH₂), 1.58(m, 2H, CH₂), 1.44 (m, 8H, aliphatic); MS (CI): 428.2 (M+H).

18(f) Methyl4-[2-thia-3-[2-(E-2-carboxy-methylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate

To a cooled (0° C.) solution of SOCl₂ (0.51 mL, 7.0 mmol) in dry toluene(2 mL) under an argon atmosphere was added a solution of2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine(300 mg, 0.70 mmol) in toluene (5 mL). After 5 minutes the cooling bathwas removed and the reaction was stirred for 2 hours at roomtemperature. The toluene and excess SOCl₂ were evaporated. To this wasadded dry DMF (2 mL), methyl 4-mercaptomethylbenzoate (180 mg, 0.7 mmol)[prepared from 4-mercaptomethylbenzoic acid (Bader and methanolic HCl],and anhydrous Cs₂ CO₃ (1.63 g, 5.0 mmol). The reaction was heated at 60°C. under an atmosphere of argon for 2 hours. Upon cooling to roomtemperature the reaction was diluted with EtOAc and washed with H₂ O,10% NaOH, H₂ O, and brine and dried (MgSO₄). Purification by flashcolumn chromatography (silica, 15% EtOAc in hexane) yielded a colorlesswaxy solid: ¹ H NMR (250 MHz, CDCl₃) δ 8.05 (d, J=15.8 Hz, 1H, olefin),7.93 (d, J=8.6 Hz, 2H, phenyl), 7.35 (d, J=8.6 Hz, 2H, phenyl), 7.18 (d,J=8.6 Hz, 1H, pyridyl), 7.06 (d, J=8.6 Hz, 1H, pyridyl), 7.02 (d, J=8.6Hz, 2H, phenyl), 6.98 (d, J=15.8 Hz, 1H, olefin), 6.78 (d, J=8.6 Hz, 2H,phenyl), 3.92 (t, J=6.5 Hz, 2H, OCH₂), 3.85 (s, 3H, methyl ester), 3.75(s, 3H, OCH₃), 3.72 (s, 3H, methyl ester), 3.64 (s, 2H, SCH₂), 3.59 (s,2H, SCH₂), 2.49 (t, J=7.6 Hz, 2H, benzylic), 1.78 (m, 2H, CH₂), 1.40 (m,10H, aliphatic); MS (CI): 592 (M+H).

18(g).4-[2-Thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt

Methyl4-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate(80 mg, 0.13 mmol) was dissolved in tetrahydrofuran (THF) (1.5 mL) andMeOH (1.5 mL) and treated with 1.0M LiOH (0.8 mL, 0.8 mmol). Thereaction was stirred under an argon atmosphere for 20 hours. The solventwas evaporated and the product purified by Reversed Phased MPLC (RP-18silica, H₂ O--MeOH gradient). Lyophilization yielded a colorlessamorphous solid ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.87 (d, J=8.6 Hz, 2H,phenyl), 7.79 (d, J=15.8 Hz, 1H, olefin), 7.34 (m, 3H, phenyl, pyridyl),7.23 (d, J=8.6 Hz, 1H, pyridyl), 7.08 (d, J=15.8 Hz, 1H, olefin), 7.06(d, J=8.6 Hz, 2H, phenyl), 6.80 (d, J=8.6 Hz, 2H, phenyl), 4.04 (t,J=6.5 Hz, 2H, OCH₂), 3.74 (s, 2H, SCH₂), 3.73 (s, 3H, OCH₃), 3.69 (s,2H, SCH₂), 2.55 (t, J=7.6 Hz, 2H, benzylic), 1.87 (m, 2H, CH₂), 1.50 (m,10H, aliphatic); Analysis calcd for C₃₂ H₃₅ NO₆ Li₂.3H₂ O: C, 61.04; H,6.56; N, 2.22; found: C, 60.96; H, 6.35; N, 2.39; MS (FAB): 576 (M+H),582.3 (M+Li).

EXAMPLE 194-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoic,acid, dilithium salt 19(a). Methyl4-[2-oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate

Methyl4-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate(110 mg, 0.186 mmol) was dissolved in dry CH₂ Cl₂ (4 mL) under an argonatmosphere and cooled to -20° C. To this was added 85%m-chloroperoxybenzoic acid (36 mg, 0.18 mmol) in two portions 15 minutesapart. The reaction was stirred for 15 minutes at -20° C. following thesecond addition and then quenched with 5% NaHCO₃. The product wasextracted into CH₂ Cl₂ and the organic extracts were dried (MgSO₄).Purification by flash column chromatography (silica, 50% EtOAc inhexane) gave a white solid: ¹ H NMR (250 MHz, CDCl₃) δ 8.10 (d, J=15.8Hz, 1H, olefin), 8.07 (d, J=8.6 Hz, 2H, phenyl), 7.50 (d, J=8.6 Hz, 2H,phenyl), 7.28 (d, J=8.6 Hz, 1H, pyridyl), 7.20 (d, J=8.6 Hz, 1H,pyridyl), 7.12 (d, J=8.6 Hz, 2H, phenyl), 7.07 (d, J=15.8 Hz, 1H,olefin), 6.83 (d, J=8.6 Hz, 2H, phenyl), 4.19 (d, J=12.8 Hz, 1H SCH),4.12 (d, J=12.8 Hz, 1H, SCH), 4.04 (t, J=6.5 Hz, 2H, OCH₂), 3.94 (s, 3H,methyl ester), 3.92 (m, 2H, SCH₂), 3.83 (s, 3H, OCH₃), 3.79 (s, 3H,methyl ester), 2.56 (t, J=7.6 Hz, 2H, benzylic), 1.87 (m, 2H, CH₂), 1.40(m, 10H, aliphatic); Analysis calcd for C₃₄ H₄₁ NO₇ S: C, 67.19; H,6.80; N, 2.30; found: C, 66.80; H, 7.12; N, 2.25; MS (CI): 608 (M+H).

19(b).4-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt

Methyl4-[2-oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate(90 mg, 0.148 mmol) was dissolved in THF (1.5 mL) and MeOH (1.5 mL) andtreated with 10M LiOH (0.8 mL, 0.8 mmol). The reaction was stirred underan argon atmosphere for 20 hours. The solvent was evaporated and theproduct purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded a colorless amorphous solid: ¹ H NMR(250 MHz, d⁴ -MeOH) δ 7.98 (d, J=8.6 Hz, 2H, phenyl), 7.81 (d, J=15.8Hz, 1H, olefin), 7.40 (d, J=8.6 Hz, 2H, phenyl), 7.39 (d, J=8.6 Hz, 1H,pyridyl), 7.27 (d, J=8.6 Hz, 1H, pyridyl), 7.09 (d, J=15.8 Hz, 1H,olefin), 7.05 (d, J=8.6 Hz, 2H, phenyl), 6.77 (d, J=8.6 Hz, 2H, phenyl),4.35 (d, J=12.8 Hz, 1H, SCH), 4.25 (d, J=12.8 Hz, 1H, SCH), 4.06 (m, 4H,OCH₂, SCH₂), 3.73 (s, 3H, OCH₃), 2.52 (t, J=7.6 Hz, 2H, benzylic), 1.86(m, 2H, CH₂), 1.55 (m, 4H, aliphatic), 1.35 (m, 6H, aliphatic); MS(FAB): 592 (M+H), 500 (M+H; free acid).

EXAMPLE 203-[2-Thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt 20(a). Methyl 3-mercaptomethylbenzoate

To a solution of methyl 3-bromomethylbenzoate (6.9 g, 30 mmol;Lancaster) in dry acetone (10 mL) was added via dropwise addition asolution of thiourea (2.28 g, 30 mmol) in dry acetone (40 mL) at roomtemperature. After 15 minutes the precipitated thiouronium salt wascollected by filtration; the solids were washed with acetone and dried.The thiouronium salt was dissolved in H₂ O (65 mL) and the pH wasadjusted to 10.5 by the addition of 10% NaOH. The mixture was refluxedfor 2 hours. After cooling to room temperature the solution wasextracted with EtOAc and the organic layer was discarded. The aqueoussolution was acidified to pH 1.5 and extracted three times with EtOAc.The organic extracts were dried (MgSO₄), filtered and the solventevaporated. The crude acid was then dissolved in anhydrous MeOH (125mL), cooled to 0° C., and dry HCl gas was bubbled through the solutionfor 30 minutes. The reaction was then left for two days at roomtemperature. The mixture was concentrated in vacuo and the product waspurified by flash column chromatography (silica, 5% EtOAc in hexane)providing a colorless oil: ¹ H NMR (250 MHz, CDCl₃) δ 8.00 (s, 1H,2-phenyl), 7.91 (d, J=7.6 Hz, 1H, 6-phenyl), 7.52 (d, J=7.6 Hz, 1H,4-phenyl), 7.39 (dd, J=7.6 Hz, 1H, 5-phenyl), 3.92 (s, 3H, methylester), 3.78 (d, J=7.7 Hz, 2H, SCH₂), 1.79 (t, J=7.7 Hz, 1H, SH).

20(b). Methyl3-[2-thia-3-[2-(E-2-carboxy-methylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate

To a cooled (0° C.) solution of SOCl₂ (2.5 mL, 35 mmol) in dry toluene(25 mL) under an argon atmosphere was added a solution of2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine(1.5 g, 3.5 mmol) in toluene (10 mL). After 5 minutes the cooling bathwas removed and the reaction was stirred for 4 hours at roomtemperature. The toluene and excess SOCl₂ were evaporated. To this wasadded dry DMF (5 mL), methyl 3-mercaptomethylbenzoate (600 mg, 3.3mmol), and anhydrous Cs₂ CO₃ (6.6 g, 20 mmol). The reaction was heatedat 60° C. under an atmosphere of argon for 1.5 hours. Upon cooling toroom temperature the reaction was diluted with EtOAc and washed with H₂O, 10% NaOH, H₂ O, and brine and dried (MgSO₄). Purification by flashcolumn chromatography (silica, 15% EtOAc in hexane) yielded a colorlesswaxy solid: ¹ H NMR (250 MHz, CDCl₃) δ 8.07 (d, J=15.8 Hz, 1H, olefin),7.99 (s, 1H, 2-phenyl), 7.90 (d, J=7.7 Hz, 1H, 6-phenyl), 7.54 (d, J=7.7Hz, 1H, 4-phenyl), 7.37 (dd, J=7.7 Hz, 1H, 5-phenyl), 7.28 (d, J=8.6 Hz,1H, pyridyl), 7.14 (d, J=8.6 Hz, 1H, pyridyl), 7.11 (d, J=8.6 Hz, 2H,phenyl), 7.08 (d, J=15.8 Hz, 1H, olefin), 6.82 (d, J=8.6 Hz, 2H,phenyl), 3.99 (t, J=6.5 Hz, 2H, OCH₂), 3.91 (s, 3H, methyl ester), 3.81(s, 3H, OCH₃), 3.78 (s, 3H, methyl ester), 3.71 (s, 2H, SCH₂), 3.68 (s,2H, SCH₂), 2.55 (t, J=7.6 Hz, 2H, benzylic), 1.78 (m, 2H, CH₂) 1.5 (m,10H, aliphatic); MS (CI): 592.2 (M+H).

20(c).3-[2-Thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt

Methyl3-[2-thia-3-[2-(E-2-carboxy-methylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate(1.5 g, 2.5 mmol) was dissolved in THF (20 mL) and MeOH (20 mL) andtreated with 1.0M LiOH (11.5 mL, 11.5 mmol). The reaction was stirredunder an argon atmosphere for 20 hours. The solvent was evaporated andthe product purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded a colorless amorphous solid: ¹ H NMR(250 MHz, d⁴ -MeOH) δ 7.96 (s, 1H, 2-phenyl), 7.85 (d, J=7.7 Hz, 1H,6-phenyl), 7.79 (d, J=15.8 Hz, 1H, olefin), 7.30 (m, 4H, 4,5-phenyl,4,5-pyridyl), 7.08 (d, J=15.8 Hz, 1H, olefin), 7.06 (d, J=8.6 Hz, 2H,phenyl), 6.80 (d, J=8.6 Hz, 2H, phenyl), 4.04 (t, J=6.5 Hz, 2H, OCH₂),3.74 (s, 2H, SCH₂), 3.73 (s, 3H, OCH₃), 3.69 (s, 2H, SCH₂), 2.55 (t,J=7.6 Hz, 2H, benzylic), 1.87 (m, 2H, CH₂), 1.50 (m, 10H, aliphatic);Analysis calcd for C₃₂ H₃₅ NO₆ SLi₂.5/4H₂ O: C, 64.32; H, 6.32; N, 2.34;found: C, 64.28; H, 6.24; N, 2.32; MS (FAB): 564.2 (M+H; free acid).

Proceeding in a similar manner, but substituting another alcohol for8-(4-methoxyphenyl)octan-1-ol, such as 4-(4-methoxyphenyl)butan-1-ol,preparing or purchasing the appropriate mercaptan and the appropriatebenzoate or aniline, the following compounds were make:

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt;

2-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt;

4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]phenylaceticacid, dilithium salt;

1-fluoro-3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6pyridyl]propyl]benzene,lithium salt

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene,lithium salt

1-fluoro-4-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene,lithium salt

3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]aniline,dilithium salt;

N-[3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenyltrifluoro-methanesulfonamide;[Mercaptan prepared by the method of Tagawa, H. and Veno, K., Chem.Pharm, Bull., 26(5), 1384 (1978)]; and

N-[3-[2-thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzene-methanesulfonamide,[Mercaptan prepared by the method of Lutter, E., Chem. Ber., 30, 1065(1897)].

EXAMPLE 213-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt and3-[2-Dioxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt 21(a). Methyl3-[2-oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoateand methyl3-[2-dioxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate

Methyl3-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate(150 mg, 0.25 mmol) was dissolved in dry CH₂ Cl₂ (5 mL) under an argonatmosphere and cooled to -20° C. To this was added 85%m-chloroperoxybenzoic acid (52 mg, 0.26 mmol) in two portions 15 minutesapart. The reaction was stirred for 25 minutes at -20° C. following thesecond addition and then quenched with 5% NaHCO₃. The product wasextracted into CH₂ Cl₂ and the organic extracts were dried (MgSO₄).Purification by flash column chromatography (silica, 20 and 50% EtOAc inhexane) gave the sulfoxide as a white solid and the sulfone as a whitesolid.

Sulfoxide: ¹ H NMR (250 MHz, CDCl₃) δ 8.07 (d, J=15.8 Hz, 1H, olefin),8.01 (s, 1H, 2-phenyl), 7.97 (d, J=7.7 Hz, 1H, 6-phenyl), 7.55 (d, J=7.7Hz, 1H, 4-phenyl), 7.46 (dd, J=7.7 Hz, 1H, 5-phenyl), 7.28 (d, J=8.6 Hz,1H, pyridyl), 7.20 (d, J=8.6 Hz, 1H, pyridyl), 7.07 (d, J=8.6 Hz, 2H,phenyl), 7.05 (d, J=15.8 Hz, 1H, olefin), 6.78 (d, J=8.6 Hz, 2H,phenyl), 4.12 (d, J=12.8 Hz, 1H, SCH), 4.05 (d, J=12.8 Hz, 1H, SCH),4.04 (t, J=6.5 Hz, 2H, OCH₂), 3.94 (s, 3H, methyl ester), 3.92 (m, 2H,SCH₂), 3.83 (s, 3H, OCH₃), 3.79 (s, 3H, methyl ester), 2.56 (t, J=7.6Hz, 2H, benzylic), 1.87 (m, 2H, CH₂), 1.40 (m, 10H, aliphatic); Analysiscalcd for C₃₄ H₄₁ NO₇ S.1/4H₂ O: C, 66.70; H, 6.83; N, 2.29; found: C,66.54; H, 6.68; N, 2.30; MS (CI): 608.2 (M+H);

Sulfone: ¹ H NMR (250 MHz, CDCl₃) δ 8.23 (s, 1H, 2-phenyl), 8.13 (d,J=15.8 Hz, 1H, olefin), 8.08 (d, J=7.7 Hz, 1H, 6-phenyl), 7.74 (d, J=7.7Hz, 1H, 4-phenyl), 7.51 (dd, J=7.7 Hz, 1H, 5-phenyl), 7.46 (d, J=8.6 Hz,1H, pyridyl), 7.24 (d, J=8.6 Hz, 1H, pyridyl), 7.12 (d, J=8.6 Hz, 2H,phenyl), 7.11 (d, J=15.8 Hz, 1H, olefin), 6.84 (d, J=8.6 Hz, 2H,phenyl), 4.30 (s, 4H, SCH₂), 4.06 (t, J=6.5 Hz, 2H, OCH₂), 3.93 (s, 3H,methyl ester), 3.83 (s, 3H, OCH₃), 3.79 (s, 3H, methyl ester), 2.56 (t,J=7.6 Hz, 2H, benzylic), 1.9 (m, 2H, CH₂), 1.5 (m, 10H, aliphatic); MS(CI): 624.2 (M+H).

21(b).3-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt

Methyl3-[2-oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate(100 mg, 0.165 mmol) was dissolved in THF (1.5 mL) and MeOH (1.5 mL) andtreated with 1.0M LiOH (0.8 mL, 0.8 mmol). The reaction was stirredunder an argon atmosphere for 20 hours. The solvent was evaporated andthe product purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded a colorless amorphous solid: ¹ H NMR(250 MHz, d⁴ -MeOH) δ 7.95 (m, 2H, 2,6-phenyl), 7.82 (d, J=15.8 Hz, 1H,olefin), 7.40 (m, 2H, 4,5-phenyl), 7.37 (d, J=8.6 Hz, 1H, pyridyl), 7.29(d, J=8.6 Hz, 1H, pyridyl), 7.10 (d, J=15.8 Hz, 1H, olefin), 7.06 (d,J=8.6 Hz, 2H, phenyl), 6.79 (d, J=8.6 Hz, 2H, phenyl), 4.36 (d, J=12.8Hz, 1H, SCH), 4.25 (d, J=12.8 Hz, 1H, SCH), 4.08 (m, 4H, OCH₂, SCH₂),3.73 (s, 3H, OCH₃), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.87 (m, 2H, CH₂),1.55 (m, 4H, aliphatic), 1.37 (m, 6H, aliphatic); Analysis calcd for C₃₂H₃₅ NO₇ SLi₂.7/4H₂ O: C, 61.68; H, 6.23; N, 2.25; found: C, 61.79; H,6.10; N, 2.39; MS (FAB): 592.2 (M+H).

This reaction was also used to prepare3-[2-oxythia-3-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoicacid, lithium salt.

21(c).3-[2-Dioxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt

Methyl3-[2-dioxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate(20 mg, 0.0321 mmol) was dissolved in THF (0.5 mL) and MeOH (0.5 mL) andtreated with 1.0M LiOH (0.2 mL, 0.2 mmol). The reaction was stirredunder an argon atmosphere for 20 hours. The solvent was evaporated andthe product purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded a colorless amorphous solid: ¹ H NMR(250 MHz, d⁴ -MeOH) δ 8.08 (s, 1H, 2-phenyl), 7.96 (d, J=7.7 Hz, 1H,6-phenyl), 7.85 (d, J=15.8 Hz, 1H, olefin), 7.58 (d, J=7.7 Hz, 1H,4-phenyl), 7.39 (m, 3H, 5-phenyl, 4,5-pyridyl), 7.13 (d, J=15.8 Hz, 1H,olefin), 7.08 (d, J=8.6 Hz, 2H, phenyl), 6.82 (d, J=8.6 Hz, 2H, phenyl),4.86 (s, 4H, SCH₂), 4.10 (t, J=6.5 Hz, 2H, OCH₂), 3.75 (s, 3H, OCH₃),2.52 (t, J=7.6 Hz, 2H, benzylic), 1.87 (m, 2H, CH₂), 1.55 (m, 4H,aliphatic), 1.40 (m, 6H, aliphatic); Analysis calcd for C₃₂ H₃₅ NO₈SLi₂.9/4H₂ O: C, 59.30; H, 6.14; N, 2.16; found: C, 59.29; H, 6.20; N,2.39; MS (FAB): 608.2 (M+H).

This reaction can also be used to make other sulfoxides and sulfones ofthis inventions including3-[2-dioxythia-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt, and3-[2-oxythia-[2-(E-2-carboxyethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt.

EXAMPLE 223-[2-Thia-3-[2-(2-carboxyethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt 22(a).2-(2-Carboxymethylethanyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-hydroxymethylpyridine

2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine(300 mg, 0.702 mmol) was dissolved in MeOH (3 mL) and treated with 5%Pd--C catalyst (30 mg). The reaction was stirred under an atmosphere ofH₂ (balloon pressure) for 5 hours. The reaction was diluted with CH₂Cl₂, and filtered through Celite, and concentrated. Purification byflash column chromatography (silica, EtOAc:CH₂ Cl₂ :hexane, 25:50:25)gave a pale yellow oil: ¹ H NMR (250 MHz, CDCl₃) δ 7.09 (m, 4H, phenyl,pyridyl), 6.80 (d, J=8.6 Hz, 2H, phenyl), 4.62 (s, 2H, CH₂), 3.93 (t,J=6.5 Hz, 2H, OCH₂), 3.77 (s, 3H, OCH₃), 3.68 (s, 3H, methyl ester),3.16 (dd, J=7.3, 7.2 Hz, 2H, CH₂), 2.77 (dd, J=7.3, 7.2 Hz, 2H, CH₂),2.54 (t, J=7.6 Hz, 2H, benzylic), 1.79 (m, 2H, CH₂), 1.57 (m, 2H, CH₂),1.44 (m, 2H, CH₂), 1.34 (m, 6H, aliphatic); MS (CI): 430.2 (M+H).

22(b). Methyl3-[2-thia-3-[2-(2-carboxymethylethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate

To a cooled (0° C.) solution of SOCl₂ (0.17 mL, 2.33 mmol) in drytoluene (1.5 mL) under an argon atmosphere was added2-(2-carboxymethylethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine(100 mg, 0.233 mmol). After 5 minutes the cooling bath was removed andthe reaction was stirred for 1.5 hours at room temperature. The tolueneand excess SOCl₂ were evaporated. To this was added dry DMF (0.5 mL),methyl 3-mercaptomethylbenzoate (47 mg, 0.258 mmol), and anhydrous Cs₂CO₃ (380 mg, 1.16 mmol). The reaction was heated at 60° C. under anatmosphere of argon for 1 hour. Upon cooling to room temperature thereaction was diluted with EtOAc and washed with H₂ O, 10% NaOH, H₂ O,and brine and dried (MgSO₄). Purification by flash column chromatography(silica, EtOAc:CH₂ Cl₂ :hexane, 15:25:65) yielded a pale yellow oil: ¹ HNMR (250 MHz, CDCl₃) δ 7.99 (s, 1H, 2-phenyl), 7.92 (d, J=7.7 Hz, 1H,6-phenyl), 7.54 (d, J=7.7 Hz, 1H, 4-phenyl), 7.37 (dd, J=7.7 Hz, 1H,5-phenyl), 7.09 (m, 4H, pyridyl, phenyl), 6.88 (d, J=8.6 Hz, 2H,phenyl), 3.93 (t, J=6.5 Hz, 2H, OCH₂), 3.91 (s, 3H, methyl ester), 3.78(s, 3H, OCH₃), 3.71 (s, 2H, SCH₂), 3.65 (s, 3H, methyl ester), 3.64 (s,2H, SCH₂), 3.14 (dd, J=7.3, 7.2 Hz, 2H, CH₂), 2.79 (dd, J=7.3, 7.2 Hz,2H, CH₂), 2.55 (t, J=7.6 Hz, 2H, benzylic), 1.80 (m, 2H, CH₂), 1.58 (m,2H, CH₂), 1.45 (m, 2H, CH₂), 1.34 (m, 6H, aliphatic); Analysis calcd forC₃₄ H₄₃ NO₆ S: C, 68.77; H, 7.30; N, 2.36; found: C, 68.87; H, 7.21; N,2.17; MS (CI): 594.6 (M+H).

22(c).3-[2-Thia-3-[2-(2-carboxyethanyl)-3-[8-(4-methoxy-phenyl)octyloxy]-6-pyridyl]propyl]benzoicacid, dilithium salt

Methyl3-[2-thia-3-[2-(2-carboxymethylethanyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]benzoate(116 mg, 0.195 mmol) was dissolved in THF (2.25 mL) and MeOH (0.75 mL)and treated with 1.0M LiOH (0.75 mL, 0.75 mmol). The reaction wasstirred under an argon atmosphere for 20 hours. The solvent wasevaporated and the product purified by Reversed Phased MPLC (RP-18silica, H₂ O--MeOH gradient). Lyophilization yielded a colorlessamorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.90 (s, 1H, 2-phenyl),7.83 (d, J=7.7 Hz, 1H, 6-phenyl), 7.34 (m, 2H, 4,5-phenyl), 7.25 (d,J=8.6 Hz, 1H, pyridyl), 7.14 (d, J=8.6 Hz, 1H, pyridyl), 7.07 (d, J=8.6Hz, 2H, phenyl), 6.83 (d, J=8.6 Hz, 2H, phenyl), 4.01 (t, J=6.5 Hz, 2H,OCH₂), 3.77 (s, 3H, OCH₃), 3.73 (s, 2H, SCH₂), 3.71 (s, 2H, SCH₂), 3.07(dd, J=7.3, 7.2 Hz, 2H, CH₂), 2.47 (m, 4H, CH₂, benzylic), 1.81 (m, 2H,CH₂), 1.50 (m, 4H, aliphatic), 1.30 (m, 6H, aliphatic); Analysis calcdfor C₃₂ H₃₇ NO₆ SLi₂.9/4H₂ O: C, 62.18; H, 6.77; N, 2.27; found: C,61.93; H, 6.48; N, 2.10; MS (ES): 566 (M+H; free acid), 564 (M-H; freeacid).

In a similiar manner, the following compounds were made:

3-[1-thia-2-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]ethyl]benzene,lithium salt;

3-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene,lithium salt; and

1-fluoro-4-[2-thia-3-[2-(2-carboxyethanyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-pyridyl]propyl]benzene,lithium salt.

EXAMPLE 234-[2-Thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylaceticacid, dilithium salt 23(a). Methyl 4-mercaptomethylphenylacetate

4-Bromomethyl-phenylacetic acid (1 g, 4.4 mmol) and thiourea (334 mg,4.4 mmol) were heated (35°-40° C.) in acetone (20 mL) until ahomogeneous solution resulted. Upon cooling to room temperature thethiouronium salt precipitated. The solvent was evaporated and theresidue suspended in H₂ O (10 mL). The pH was adjusted to 12 with 10%NaOH. The mixture was then refluxed for two hours. The solution wasacidified with 6N HCl and the product was extracted into EtOAc. Theorganic extracts were washed with H₂ O and dried (MgSO₄). The crude acidwas dissolved in MeOH (20 mL) and treated with conc. H₂ SO₄ (0.33 mL);the reaction was refluxed for 1.5 hours. Upon cooling to roomtemperature the reaction was diluted with H₂ O and the product wasextracted into EtOAc. The organic extracts were washed with H₂ O anddried (MgSO₄). The methyl ester was obtained as an oil; crude productwas used without further purification: ¹ H NMR (250 MHz, CDCl₃) δ 7.23(m, 4H, aryl), 3.71 (d, J=7.6 Hz, 2H, SCH₂), 3.68 (s, 3H, methyl ester),3.60 (s, 2H, CH₂), 1.74 (t, J=7.6 Hz, 1H, SH); IR film) n_(max) 2570(SH), 1740 (CO) cm⁻¹.

23(b). Methyl4-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylacetate

To a cooled (0° C.) solution of SOCl₂ (0.44 mL, 6.2 mmol) in dry toluene(7 mL) under an argon atmosphere was added2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine(270 mg, 0.62 mmol). After 5 minutes the cooling bath was removed andthe reaction was stirred for 2 hours at room temperature. The tolueneand excess SOCl₂ were evaporated. To this was added dry DMF (3 mL),methyl 4-mercaptomethylphenylacetate (183 mg, 0.93 mmol), and anhydrousCs₂ CO₃ (907 mg, 2.79 mmol). The reaction was heated at 60° C. under anatmosphere of argon for 1 hour. Upon cooling to room temperature thereaction was diluted with EtOAc and washed with H₂ O, 10% NaOH, H₂ O,and brine and dried (MgSO₄). Purification by flash column chromatography(silica, 20% EtOAc in hexane) yielded a pale yellow oil: ¹ H NMR (250MHz, CDCl₃) δ 8.08 (d, J=15.8 Hz, 1H, olefin), 7.22 (m, 6H, phenyl,pyridyl), 7.12 (d, J=8.6 Hz, 2H, phenyl), 7.07 (d, J=15.8 Hz, 1H,olefin), 6.83 (d, J=8.6 Hz, 2H, phenyl), 4.00 (t, J=6.5 Hz, 2H, OCH₂),3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OCH₃), 3.70 (s, 3H, methylester), 3.68 (s, 2H, SCH₂), 3.67 (s, 2H, SCH₂), 3.62 (s, 2H, CH₂), 2.55(t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH₂), 1.60 (m, 2H, CH₂), 1.50(m, 2H, CH₂), 1.37 (m, 6H, aliphatic); MS (CI): 605 (M+H).

23(c).4-[2-Thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylaceticacid, dilithium salt

Methyl4-[2-thia-3-[2-(E-2-carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylacetate(100 mg, 0.165 mmol) was dissolved in THF (1.4 mL) and MeOH (0.5 mL) andtreated with 1.0M LiOH (0.5 mL, 0.5 mmol). The reaction was stirredunder an argon atmosphere for 20 hours. The solvent was evaporated andthe product purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded a colorless amorphous solid: ¹ H NMR(250 MHz, d⁴ -MeOH) δ 7.76 (d, J=15.8 Hz, 1H, olefin), 7.21 (m, 6H,phenyl, pyridyl), 7.06 (d, J=8.6 Hz, 2H, phenyl), 7.05 (d, J=15.8 Hz,1H, olefin), 6.77 (d, J=8.6 Hz, 2H, phenyl), 4.02 (t, J=6.5 Hz, 2H,OCH₂), 3.72 (s, 3H, OCH₃), 3.66 (s, 4H, SCH₂), 3.44 (s, 2H, CH₂), 2.51(t, J=7.6 Hz, 2H, benzylic), 1.86 (m, 2H, CH₂), 1.53 (m, 4H, aliphatic),1.34 (m, 6H, aliphatic); MS (FAB): 578.2 (M+H; free acid).

EXAMPLE 244-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylaceticacid, dilithium salt 24(a). Methyl4-[2-oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylacetate

Methyl4-[2-thia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylacetate(171 mg, 0.28 mmol) was dissolved in dry CH₂ Cl₂ (5 mL) under an argonatmosphere and cooled to -10° C. To this was added 85%m-chloroperoxybenzoic acid (67 mg, 0.31 mmol) in two portions 15 minutesapart. The reaction was stirred for 20 minutes at -10° C. following thesecond addition and then quenched with aq NaHCO₃. The product wasextracted into EtOAc and the organic extracts were washed with H₂ O andbrine and dried (MgSO₄). Purification by flash column chromatography(silica, 30% EtOAc in hexane) gave the sulfoxide as a white solid: ¹ HNMR (250 MHz, CDCl₃) δ 8.00 (d, J=15.8 Hz, 1H, olefin), 7.30 (d, J=8.2Hz, 2H, phenyl), 7.23 (d, J=8.2 Hz, 2H, phenyl), 7.20 (d, J=8.6 Hz, 1H,pyridyl), 7.13 (d, J=8.6 Hz, 1H, pyridyl), 7.01 (d, J=8.6 Hz, 2H,phenyl), 6.98 (d, J=15.8 Hz, 1H, olefin), 6.76 (d, J=8.6 Hz, 2H,olefin), 4.05 (d, J=12.9 Hz, 1H, SCH), 4.02 (d, J=12.9 Hz, 1H, SCH),3.94 (t, J=6.5 Hz, 2H, OCH₂), 3.83 (d, J=12.9 Hz, 1H, SCH), 3.80 (d,J=12.9 Hz, 1H, SCH), 3.74 (s, 3H, methyl ester (m 3.70 (s, 3H, OCH₃),3.62 (s, 3H, methyl ester), 3.56 (s, 2H, CH₂), 2.47 (t, J=7.6 Hz, 2H,benzylic), 1.78 (m, 2H, CH₂), 1.57 (m, 2H, CH₂), 1.39 (m, 2H, CH₂), 1.28(m, 6H, aliphatic); MS (FAB): 622.3 (M+H); mp 87°-89° C.

24(b).4-[2-Oxythia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenylaceticacid, dilithium salt

Methyl4-[2-oxythia-3-[2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]-propyl]phenylacetate(110 mg, 0.177 mmol) was dissolved in THF (1.0 mL) and MeOH (0.53 mL)and treated with 1.0M LiOH (0.53 mL, 0.53 mmol). The reaction wasstirred under an argon atmosphere for 20 hours. The solvent wasevaporated and the product purified by Reversed Phased MPLC (RP-18silica, H₂ O--MeOH gradient). Lyophilization yielded a colorlessamorphous solid: ¹ H NMR (250 MHz, d⁴ -MeOH) δ 7.79 (d, J=15.8 Hz, 1H,olefin), 7.34 (m, 6H, phenyl, pyridyl), 7.09 (d, J=15.8 Hz, 1H, olefin),7.06 (d, J=8.6 Hz, 2H, phenyl), 6.79 (d, J=8.6 Hz, 2H, phenyl), 4.29 (d,J=12.9 Hz, 1H, SCH), 4.18 (d, J=12.9 Hz, 1H, SCH), 4.04 (m, 4H, SCH₂,OCH₂), 3.73 (s, 3H, OCH₃), 3.48 (s, 2H, CH₂), 2.55 (t, J=7.6 Hz, 2H,benzylic), 1.85 (m, 2H, CH₂), 1.55 (m, 4H, aliphatic), 1.35 (m, 6H,aliphatic); MS (FAB): 606.3 (M+H), 594.4 (M+H; free acid).

EXAMPLE 253-[2-Thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl]-N,N-dimethylbenzamide,lithium salt 25(a).3-[2-Thia-3-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl]benzoicacid

To a cooled (0° C.) solution of SOCl₂ (0.85 mL, 11.7 mmol) in drytoluene (5 mL) under an argon atmosphere was added a solution of2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine(500 mg, 1.17 mmol) in toluene (6 mL). After 5 minutes the cooling bathwas removed and the reaction was stirred for 2 hours at roomtemperature. The toluene and excess SOCl₂ were evaporated. To this wasadded dry DMF (2 mL), 3-mercaptomethyl-benzoic acid (216 mg, 1.29 mmol)in DMF (2 mL), and anhydrous Cs₂ CO₃ (3.8 g, 11.7 mmol). The reactionwas heated at 60° C. under an atmosphere of argon for 6 hours. Uponcooling to room temperature the reaction was diluted with H₂ O andwashed with EtOAc. The aqueous phase was acidified to pH 1.2 andextracted with EtOAc. The combined organic extracts were washed with H₂O, and brine and dried (MgSO₄). Purification by flash columnchromatography (silica, 5% MeOH in CH₂ Cl₂) yielded a pale yellow oil: ¹H NMR (250 MHz, CDCl₃) δ 8.07 (d, J=15.7 Hz, 1H, olefin), 8.05 (s, 1H,2-phenyl), 7.96 (d, J=7.6 Hz, 1H, 6-phenyl), 7.58 (d, J=7.6 Hz, 1H,4-phenyl), 7.39 (dd, J=7.6 Hz, 1H, 5-phenyl), 7.24 (d, J=8.6 Hz, 1H,pyridyl), 7.13 (d, J=8.6 Hz, 1H, pyridyl), 7.08 (d, J=8.6 Hz, 2H,phenyl), 7.06 (d, J=15.7 Hz, 1H, olefin), 6.82 (d, J=8.6 Hz, 2H,phenyl), 4.01 (t, J=6.5 Hz, 2H, O--CH₂), 3.81 (s, 3H, methyl ester),3.78 (s, 3H, OMe), 3.72 (s, 2H, S--CH₂), 3.69 (s, 2H, S--CH₂), 2.52 (t,J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH₂), 1.57 (m, 2H, CH₂), 1.49 (m,2H, CH₂), 1.35 (m, 6H, aliphatic).

25(b).3-[2-Thia-3-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl]-N,N-dimethylbenzamide

3-[2-Thia-3-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl]benzoicacid (98 mg, 0.17 mmol) was dissolved in SOCl₂ (5 mL) and refluxed for 1hour. The excess SOCl₂ was removed in vacuo. The resulting acid chloridewas dissolved in dry CH₂ Cl₂ (5 mL), cooled to 0° C., and treated withtriethylamine (52 mL, 0.37 mmol). Diethylamine was then introduced intothe reaction via a cooling finger; reaction was stirred for 15 minutes.The solvent was removed in vacuo and the product was purified by flashcolumn chromatography (silica, 35% EtOAc in hexane) to give a paleyellow oil: ¹ H NMR (250 MHz, CDCl₃) δ 8.07 (d, J=15.7 Hz, 1H, olefin),7.38 (m, 4H, 4,5,6-phenyl, pyridyl), 7.29 (s, 1H, 2-phenyl), 7.20 (d,J=8.6 Hz, 1H, pyridyl), 7.11 (d, J=8.6 Hz, 2H, phenyl), 7.03 (d, J=15.7Hz, 1H, olefin), 6.82 (d, J=8.6 Hz, 2H, phenyl), 4.02 (t, J=6.5 Hz, 2H,O--CH₂), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.70 (s, 2H,S--CH₂), 3.68 (s, 2H, S--CH₂), 3.12 (s, 3H, N--Me), 2.97 (s, 3H, N--Me),2.55 (t, J=7.6 Hz, 2H, benzylic), 1.86 (m, 2H, CH₂), 1.6-1.3 (m, 10H,aliphatic).

25(c).3-[2-Thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]propyl]-N,N-dimethylbenzamide,lithium salt

3-[2-Thia-3-[2-(E-2-carboxymethylethenyl)-3-(8-(4-methoxyphenyl)octyloxy-6-pyridyl]propyl]-N,N-dimethylbenzamide(80 mg, 0.132 mmol) was dissolved in THF (1.5 mL) and MeOH (1.5 mL) andtreated with 1.0M LiOH (0.4 mL, 0.4 mmol). The reaction was stirredunder an argon atmosphere for 24 hours. The solvent was evaporated andthe product purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded a colorless amorphous solid: ¹ H NMR(250 MHz, d⁴ -MeOH) δ 7.79 (d, J=15.7 Hz, 1H, olefin), 7.33 (m, 6H,2,4,5,6-phenyl, 4,5-pyridyl), 7.07 (d, J=8.6 Hz, 2H, phenyl), 7.05 (d,J=15.7 Hz, olefin), 6.80 (d, J=8.6 Hz, 2H, phenyl), 4.03 (t, J=6.5 Hz,2H, O--CH₂), 3.76 (s, 2H, S--CH₂), 3.74 (s, 3H, OMe), 3.69 (s, 2H,S--CH₂), 3.09 (s, 3H, N--Me), 2.97 (s, 3H, N--Me), 2.52 (t, J=7.6 Hz,2H, benzylic), 1.86 (m, 2H, CH₂), 1.54 (m, 4H, aliphatic), 1.36 (m, 6H,aliphatic).

EXAMPLE 265-[3-[2-Thia-3-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]propyl]phenyl]tetrazole,dilithium salt

This tetrazole is prepared via the acid chloride described aboveaccording to Duncia, Pierce, and Santella, J. Org. Chem., 1991, 56,2395-2400.

EXAMPLE 26bis (E)-Sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[phenylthiomethyl]-2-pyridinyl]-2-propenoate26bis(a) (E)-Methyl3-[3-[4-(4-methoxyphenyl)butyloxy]-6-]phenylthiomethyl]-2-pyridinyl]-2-propenoate

Thiophenol (0.017 mL, 0.166 mmol) was dissolved in dry MeCN (0.30 mL)and treated with2-(E-2-carboxymethylethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-chloromethylpyridinehydrochloride (65 mg, 0.152 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU, 0.08 mL, 0.532 mmol). The reaction was stirred under an atmosphereof argon at 50° C. for 3 h. The reaction solution was diluted with EtOAcand washed with H₂ O and brine and dried (MgSO₄). Purification by flashcolumn chromatography (silica, EtOAc:CH₂ Cl₂ :hexane, 10:15:75) gave acolorless waxy solid; ¹ H NMR (250 MHz, CDCl₃) δ 8.04 (d, J=15.7 Hz, 1H,vinyl), 7.36-7.07 (m, 9H, aryl), 6.99 (d, J=15.7 Hz, 1H, vinyl), 6.83(d, J=8.7 Hz, 2H, phenyl), 4.21 (s, 2H, CH₂ --S), 3.97 (t, J=6.1 Hz, 2H,CH₂ --O), 3.81 (s, 3H, OMe), 3.78 (s, 3H, methyl ester), 2.64 (t, J=7.2Hz, 2H, benzylic), 1.81 (m, 4H, CH₂ CH₂), analysis calcd. for C₂₇ H₂₉NO₄ S.3/8H₂ O: C, 68.95; H, 6.38; N, 2.98; found: C, 68.89; H, 6.23; N,2.94; MS (ES+): 464.2 (M+H).

26bis(b) (E)-Sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[phenylthiomethyl]-2-pyridinyl]-2-propenoate

(E)-Methyl3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[phenylthiomethyl]-2-pyridinyl]-2-propenoate(55 mg, 0.119 mmol) was dissolved in THF (1.0 mL) and MeOH (0.30 mL) andtreated with 1.0M NaOH (0.25 mL, 0.25 mmol). The reaction was stirredunder an argon atmosphere for 20 h. The solvent was evaporated and theproduct purified by Reversed Phased MPLC (RP-18 silica, H₂ O--MeOHgradient). Lyophilization yielded the captioned product as a colorlessamorphous solid: ¹ H NMR (250 MHz, d⁶ -DMSO) δ 7.42 (d, J=15.7 Hz, 1H,vinyl), 7.40-7.20 (m, 7H, aryl), 7.12 (d, J=8.7 Hz, 2H, phenyl), 6.83(d, J=8.7 Hz, 2H, phenyl), 6.82 (d, J=15.7 Hz, 1H, vinyl), 4.26 (s, 2H,CH₂ --S), 4.01 (t, J=6.1 Hz, 2H, CH₂ --O), 3.71 (s, 3H, OMe), 2.61 (t,J=7.2 Hz, 2H, benzylic), 1.73 (m, 4H, CH₂ CH₂); analysis calcd. for C₂₆H₂₆ NO₄ SNa.3/4H₂ O: C, 64.38; H, 5.71; N, 2.89; found: C, 64.46; H,6.04; N, 2.97; MS (ES+): 450.2 (M+H, free acid), (ES-): 448.0 (M-H, freeacid).

Proceeding in a similar manner, the following compounds were made:

(E)-lithium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[2-chlorophenylthio)methyl]-2pyridinyl]-2-propenoate

(E)-lithium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(3,4-dichlorophenylthio)methyl]-2-pyridinyl]-2propenoate.

(E)-lithium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(4-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(4-fluorophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(3-chlorophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2-chlorobenzylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2-methoxyphenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2,4-dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2-bromophenylthio)methyl]-2-pyridinyl]-2-propenoate,

(E)-sodium3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2-methylphenylthio)methyl]-2-pyridinyl]-2propenoate.

EXAMPLE 27

Formulations for pharmaceutical use incorporating compounds of thepresent invention can be prepared in various forms and with numerousexcipients. Means for making various formulations can be found instandard texts such as Remington's Pharmaceutical Sciences, and similarpublications and compendia. Specific examples of formulations are givenbelow.

    ______________________________________                                        Tablets                                                                                                     Per 10,000                                      Ingredients         Per Tablet                                                                              Tablets                                         ______________________________________                                        1. Active ingredient (Cmpd of                                                                     40      mg    400   g                                     Form. I)                                                                      2. Corn Starch      20      mg    200   g                                     3. Alginic acid     20      mg    200   g                                     4. Sodium alginate  20      mg    200   g                                     5. Magnesium stearate                                                                             1.3     mg    13    g                                                         101.3   mg    1013  g                                     ______________________________________                                    

Procedure for making tablets:

Step 1. Blend ingredients No 1, No. 2, No. 3 and No. 4 in a suitablemixer/blender.

Step 2. Add sufficient water portionwise to the blend from Step 1 withcareful mixing after each addition. Such additions of water and mixinguntil the mass is of a consistency to permit its conversion to wetgranules.

Step 3. The wet mass is converted to granules by passing it through anoscillating granulator using a No. 8 mesh (2.38 mm) screen.

Step 4. The wet granules are then dried in an oven at 410° F. (60° C.)until dry.

Step 5. The dry granules are lubricated with ingredient No. 5.

Step 6. The lubricated granules are compressed on a suitable tabletpress.

    ______________________________________                                        Suppositories:                                                                Ingredients         Per Supp. Per 100 Supp.                                   ______________________________________                                        1. Formula I compound Active                                                                      4.0    mg     40    g                                     ingredient                                                                    2. Polyethylene Glycol 1000                                                                       135.0  mg     1,350 g                                     3. polyethylene glycol 4000                                                                       45.0   mg     450   g                                                         184.0  mg     1,840 g                                     ______________________________________                                    

Procedure:

Step 1. Melt ingredient No. 2 and No. 3 together and stir until uniform.

Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1 andstir until uniform.

Step 3. Pour the molten mass from Step 2 into suppository moulds andchill.

Step 4. Remove the suppositories from moulds and wrap.

EXAMPLE 28 Inhalation Formulation

A compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic salineand aerosolized from a nebulizer operating at an air flow adjusted todeliver the desired amount of drug per use.

EXAMPLE 29 Topical Formulations

Formulations for pharmaceutical use incorporating compounds of thepresent invention can be prepared in various forms and with numerousexcipients. Means for making various formulations can be found instandard texts such as Remington's Pharmaceutical Sciences, and similarpublications and compendia. Specific examples of formulations are givenbelow.

    ______________________________________                                        Ointments                                                                     Hydrophyllic Petrolatum                                                       Ingredients   Amount (% Weight/weight)                                        ______________________________________                                        Cholesterol   30.0 g                                                          Stearyl Alcohol                                                                             30.0 g                                                          White Wax     78.0 g                                                          Active Ingredient                                                                            2.0 g                                                          White Petolatum                                                                             860.0 g                                                         ______________________________________                                    

The stearyl alcohol, white wax and white petrolatum are melted together(steam bath for example) and cholesterol and the active ingredient areadded. Stirring is commenced and continued until the solids disappear.The source of heat is removed and the mix allowed to congeal andpackaged in metal or plastic tubes.

    ______________________________________                                        Emulsion Ointment                                                             Ingredients         Amount (% W/W)                                            ______________________________________                                        Methylparaben       0.25 g                                                    Propylparaben       0.15                                                      Sodium Lauryl Sulfate                                                                             10.0 g                                                    Active Ingredient   5.0 g                                                     Propylene Glycol    120.0 g                                                   Stearyl Alcohol     250.0 g                                                   White Petrolatum    250.0 g                                                   Purified Water      QS to 1000.0 g                                            ______________________________________                                    

The stearyl alcohol and white petrolatum are combined over heat. Otheringredients are dissolved in water, then this solution is added to thewarm (ca 50° to 100° C.) alcohol/petrolatum mixture and stirred untilthe mixture congeals. It can then be packed in tubes or anotherappropriate package form.

What is claimed is:
 1. A compound of formula I ##STR9## or an N-oxide,or a pharmaceutically acceptable salt where Z is O,m is 0-5; R is C₁ toC₂₀ -aliphatic, unsubstituted or substituted phenyl C₁ to C₁₀ -aliphaticwhere substituted phenyl has one or more radicals selected from thegroup consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo,or R is C₁ to C₂₀ -aliphatic-O--, or R is unsubstituted or substitutedphenyl C₁ to C₁₀ -aliphatic-O-- where substituted phenyl has one or moreradicals selected from the group consisting of lower alkoxy, loweralkyl, trihalomethyl, and halo; R₁ is --(C₁ to C₅ aliphatic)R₄, --(C₁ toC₅ aliphatic)CHO, --(C₁ to C₅ aliphatic)CH₂ OR₈, --R₄, --CH₂ OH, or CHO;R₂ is H, halo, lower alkyl, lower alkoxy, --CN, --(CH₂)_(n) R₄,--CH(NH₂)(R₄), or --(CH₂)_(n) R₉ where n is 0-5 and where R₉ is --N(R₇)₂where each R₇ is independently H, or an aliphatic group of 1 to 10carbon atoms, or acyl of 1-6 carbon atoms, or a cycloalkyl-(CH₂)_(n)-group of 4 to 10 carbons where n is 0-3, or both R₇ groups form a ringhaving 4 to 6 carbons; or R₃ is hydrogen, lower alkyl, lower alkoxy,halo, --CN, R₄, NHCONH₂, or OH; each R₄ group is independently --COR₅where R₅ is --OH, a pharmaceutically acceptable ester-forming group--OR₆, or --OX where X is a pharmaceutically acceptable cation, or R₅ is--N(R₇)₂ where each R₇ is independently H, or an aliphatic group of 1 to10 carbon atoms, or a cycloalkyl-(CH₂)_(n) -group of 4 to 10 carbonswhere n is 0-3, or both R₇ groups form a ring having 4 to 6 carbons, orR₄ is a sulfonamide, or tetrazol-5-yl; and R₈ is hydrogen, C₁ to C₆alkyl, or C₁ to C₆ -acyl, excluding those compounds where R₂ and R₃ areother than hydrogen and are substituted in the 2 and 6 positions.
 2. Acompound of claim 1 where m is 0 or
 1. 3. A compound of claim 2 where Ris alkoxy of 8 to 15 carbon atoms or unsubstituted or substitutedpheny-C₁ to C₁₀ -alkyl-O-- where substituted phenyl is substituted withfluoro, trifluoromethyl or methoxy and R₁ is R₄ CH═CH-- or R₄ CH₂ CH₂--.
 4. A compound of claim 3 whichis3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]benzoicacid,3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]benzoicacid, or the N-oxide, or3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octan-1-yl]-6-pyridyl]ethyl]benzoicacid, its dilithium salt, the free acid, or a pharmaceuticallyacceptable salt.
 5. A compound of claim 1 where R₂ is --(CH₂)_(n) R₉where n is 0, 1 or
 2. 6. A compound of claim 3 whichis3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]aniline,lithium salt, or5-carboxy-3-[1-oxa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]anilinedilithium salt.
 7. A pharmaceutical composition comprising an effectiveamount of a compound of formula I according to claim 1 and apharmaceutically acceptable excipient.
 8. The composition of claim 7 foruse in treating psoriasis.